View source for G protein-coupled receptor

{{short description|Class of cell surface receptors coupled to G-protein-associated intracellular signaling}}
{{Redirect|GPCR|the Great Proletarian Cultural Revolution|Cultural Revolution}}
{{Use dmy dates|date=November 2017}}
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{{Infobox protein family
| Symbol = 7tm_1
| Name = GPCR
| image = Beta-2-adrenergic-receptor.png
| width =
| caption = The human [[beta-2 adrenergic receptor]] in complex with the partial [[inverse agonist]] [[carazolol]]<ref name="Cherezov_2007"/>
| Pfam = PF00001
| Pfam_clan = CL0192
| ECOD = 5001.1.1
| InterPro = IPR000276
| SMART =
| PROSITE = PDOC00210
| MEROPS =
| SCOP =
| TCDB = 9.A.14
| OPM family = 6
| OPM protein = 1gzm
| CAZy =
| CDD = cd14964
}}

[[File:PDB 1hzx 7TM Sketch Membrane.png|thumb|The seven-transmembrane α-helix structure of [[bovine]] rhodopsin]]

'''G protein-coupled receptors''' ('''GPCRs'''), also known as '''seven-(pass)-transmembrane domain receptors''', '''7TM receptors''', '''heptahelical receptors''', '''serpentine receptors''', and '''G protein-linked receptors''' ('''GPLR'''), form a large [[protein family|group of evolutionarily related proteins]] that are [[cell surface receptor]]s that detect [[molecule]]s outside the [[cell (biology)|cell]] and activate cellular responses. They are coupled with [[G protein]]s. They pass through the [[cell membrane]] seven times in the form of six loops<ref name="Zhang2013" /> (three&nbsp;extracellular loops interacting with [[ligand]] molecules, three intracellular loops interacting with G proteins, an [[N-terminus|N-terminal]] extracellular region and a [[C-terminal]] intracellular region<ref name="Zhang2013">{{cite book | vauthors = Zhang JV, Li L, Huang Q, Ren PG |chapter=Chapter Three - Obestatin Receptor in Energy Homeostasis and Obesity Pathogenesis |date=2013-01-01 |chapter-url=https://www.sciencedirect.com/science/article/pii/B9780123869333000030 |title=Progress in Molecular Biology and Translational Science |volume=114 |pages=89–107 | veditors = Tao YX |access-date=2023-10-24 |url-status=live |archive-url=https://web.archive.org/web/20230117153353/https://www.sciencedirect.com/science/article/abs/pii/B9780123869333000030 |archive-date=2023-01-17 |series=G Protein-Coupled Receptors in Energy Homeostasis and Obesity Pathogenesis |publisher=Academic Press  |doi=10.1016/B978-0-12-386933-3.00003-0|pmid=23317783 |isbn=978-0-12-386933-3 }}</ref>) of [[amino acid residue]]s, which is why they are sometimes referred to as seven-transmembrane receptors.<ref name="Trzaskowski2012">{{cite journal | vauthors = Trzaskowski B, Latek D, Yuan S, Ghoshdastider U, Debinski A, Filipek S | title = Action of molecular switches in GPCRs--theoretical and experimental studies | journal = Current Medicinal Chemistry | volume = 19 | issue = 8 | pages = 1090–109 | year = 2012 | pmid = 22300046 | pmc = 3343417 | doi = 10.2174/092986712799320556}} [[File:CC0-icon-80x15.png|50px]] Text was copied from this source, which is available under a [https://web.archive.org/web/20110222034809/https://creativecommons.org/licenses/by/2.5/ Attribution 2.5 Generic (CC BY 2.5) licence]</ref> Ligands can bind either to the extracellular N-terminus and loops (e.g. glutamate receptors) or to the binding site within transmembrane helices ([[rhodopsin]]-like family). They are all activated by [[agonist]]s, although a spontaneous auto-activation of an empty receptor has also been observed.<ref name="Trzaskowski2012" />

G protein-coupled receptors are found only in [[eukaryote]]s, including [[yeast]], and [[choanoflagellate]]s.<ref name="pmid12869759">{{cite journal | vauthors = King N, Hittinger CT, Carroll SB | title = Evolution of key cell signaling and adhesion protein families predates animal origins | journal = Science | volume = 301 | issue = 5631 | pages = 361–3 | date = July 2003 | pmid = 12869759 | doi = 10.1126/science.1083853 | bibcode = 2003Sci...301..361K | s2cid = 9708224 }}</ref> The [[ligand (biochemistry)|ligands]] that bind and activate these receptors include light-sensitive compounds, [[odor]]s, [[pheromone]]s, [[hormone]]s, and [[neurotransmitter]]s. They vary in size from small molecules to [[peptide]]s, to large [[protein]]s. G protein-coupled receptors are involved in many diseases.

There are two principal signal transduction pathways involving the G protein-coupled receptors:
* the [[cyclic adenosine monophosphate|cAMP]] signal pathway and
* the [[phosphatidylinositol]] signal pathway.<ref name="Gilman_1987">{{cite journal | vauthors = Gilman AG | title = G proteins: transducers of receptor-generated signals | journal = Annual Review of Biochemistry | volume = 56 | issue = 1 | pages = 615–49 | year = 1987 | pmid = 3113327 | doi = 10.1146/annurev.bi.56.070187.003151 }}</ref>
When a ligand binds to the GPCR it causes a conformational change in the GPCR, which allows it to act as a [[guanine nucleotide exchange factor]] (GEF). The GPCR can then activate an associated [[G protein]] by exchanging the [[guanosine diphosphate|GDP]] bound to the G protein for a [[guanosine triphosphate|GTP]]. The G protein's α subunit, together with the bound GTP, can then dissociate from the β and γ subunits to further affect intracellular signaling proteins or target functional proteins directly depending on the α subunit type ([[Gs alpha subunit|G<sub>αs</sub>]], [[Gi alpha subunit|G<sub>αi/o</sub>]], [[Gq alpha subunit|G<sub>αq/11</sub>]], [[G12/G13 alpha subunits|G<sub>α12/13</sub>]]).<ref name="Wettschureck_2005">{{cite journal | vauthors = Wettschureck N, Offermanns S | title = Mammalian G proteins and their cell type specific functions | journal = Physiological Reviews | volume = 85 | issue = 4 | pages = 1159–204 | date = October 2005 | pmid = 16183910 | doi = 10.1152/physrev.00003.2005 }}</ref>{{rp|1160}}

GPCRs are an important drug target, and approximately 34%<ref name="Hauser_2018">{{cite journal | vauthors = Hauser AS, Chavali S, Masuho I, Jahn LJ, Martemyanov KA, Gloriam DE, Babu MM | title = Pharmacogenomics of GPCR Drug Targets | journal = Cell | volume = 172 | issue = 1–2 | pages = 41–54.e19 | date = January 2018 | pmid = 29249361 | pmc = 5766829 | doi = 10.1016/j.cell.2017.11.033 }}</ref> of all Food and Drug Administration (FDA) approved drugs target 108 members of this family.  The global sales volume for these drugs is estimated to be 180 billion US dollars {{As of|lc=y|1=2018}}.<ref name="Hauser_2018"/> It is estimated that GPCRs are targets for about 50% of drugs currently on the market, mainly due to their involvement in signaling pathways related to many diseases i.e. mental, metabolic including endocrinological disorders, immunological including viral infections, cardiovascular, inflammatory, senses disorders, and cancer. The long ago discovered association between GPCRs and many endogenous and exogenous substances, resulting in e.g. analgesia, is another dynamically developing field of the pharmaceutical research.<ref name="Trzaskowski2012" />

==History and significance==
With the determination of the first structure of the complex between a G-protein coupled receptor (GPCR) and a G-protein trimer (Gαβγ) in 2011 a new chapter of GPCR research was opened for structural investigations of global switches with more than one protein being investigated. The previous breakthroughs involved determination of the [[crystal structure]] of the first GPCR, rhodopsin, in 2000 and the crystal structure of the first GPCR with a diffusible ligand (β<sub>2</sub>AR) in 2007. The way in which the seven transmembrane helices of a GPCR are arranged into a bundle was suspected based on the low-resolution model of frog rhodopsin from [[cryogenic electron microscopy]] studies of the two-dimensional crystals. The crystal structure of rhodopsin, that came up three years later, was not a surprise apart from the presence of an additional cytoplasmic helix H8 and a precise location of a loop covering retinal binding site. However, it provided a scaffold which was hoped to be a universal template for homology modeling and drug design for other GPCRs – a notion that proved to be too optimistic.{{citation needed|date=April 2025}}

Results 7 years later were surprising because the crystallization of β<sub>2</sub>-adrenergic receptor (β<sub>2</sub>AR) with a diffusible ligand revealed quite a different shape of the receptor extracellular side than that of rhodopsin. This area is important because it is responsible for the ligand binding and is targeted by many drugs. Moreover, the ligand binding site was much more spacious than in the rhodopsin structure and was open to the exterior. In the other receptors crystallized shortly afterwards the binding side was even more easily accessible to the ligand. New structures complemented with biochemical investigations uncovered mechanisms of action of molecular switches which modulate the structure of the receptor leading to activation states for agonists or to complete or partial inactivation states for inverse agonists.<ref name="Trzaskowski2012" />

The 2012 [[Nobel Prize in Chemistry]] was awarded to [[Brian Kobilka]] and [[Robert Lefkowitz]] for their work that was "crucial for understanding how G protein-coupled receptors function".<ref name="Nobel committee,2012">{{cite news|vauthors=((Royal Swedish Academy of Sciences))|title=The Nobel Prize in Chemistry 2012 Robert J. Lefkowitz, Brian K. Kobilka|url=https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/press.html|access-date=10 October 2012|date=10 October 2012}}</ref> There have been at least [[List of Nobel laureates in Physiology or Medicine|seven other Nobel Prizes]] awarded for some aspect of G protein–mediated signaling. As of 2012, two of the top ten global best-selling drugs ([[fluticasone propionate/salmeterol|Advair Diskus]] and [[aripiprazole|Abilify]]) act by targeting G protein-coupled receptors.<ref name="urlwww.imshealth.com">{{cite journal | vauthors = Lindsley CW | title = The top prescription drugs of 2012 globally: biologics dominate, but small molecule CNS drugs hold on to top spots | journal = ACS Chemical Neuroscience | volume = 4 | issue = 6 | pages = 905–7 | date = June 2013 | pmid = 24024784 | pmc = 3689196 | doi = 10.1021/cn400107y }}</ref>

==Classification==
[[File:GPCR classification.svg|right|thumb|Classification Scheme of GPCRs in 2006. Since this time, more genes have been found. Class A (Rhodopsin-like), Class B (Secretin-like), Class C (Glutamate Receptor-like), Others (Adhesion (33), Frizzled (11), Taste type-2 (25), unclassified (23)).<ref name="pmid16753280">{{cite journal | vauthors = Bjarnadóttir TK, Gloriam DE, Hellstrand SH, Kristiansson H, Fredriksson R, Schiöth HB | title = Comprehensive repertoire and phylogenetic analysis of the G protein-coupled receptors in human and mouse | journal = Genomics | volume = 88 | issue = 3 | pages = 263–73 | date = September 2006 | pmid = 16753280 | doi = 10.1016/j.ygeno.2006.04.001 | doi-access =  }}</ref>]]

The exact size of the GPCR superfamily is unknown, but at least 831 different [[human]] [[genes]] (or about 4% of the entire [[Protein biosynthesis|protein-coding]] [[genome]]) have been predicted to code for them from genome [[sequence analysis]].<ref name="pmid16753280"/><ref>{{Cite web|url=https://www.uniprot.org/uniprot/?query=keyword:%22G-protein%20coupled%20receptor%20%5BKW-0297%5D%22&fil=organism:%22Homo+sapiens+(Human)+%5B9606%5D%22|archive-url=https://web.archive.org/web/20200915221807/https://www.uniprot.org/uniprot/?query=keyword:%22G-protein%20coupled%20receptor%20%5BKW-0297%5D%22&fil=organism:%22Homo+sapiens+(Human)+%5B9606%5D%22|archive-date=2020-09-15|title=keyword:"G-protein coupled receptor [KW-0297]" AND organism:"Homo sapiens (Human) [9606]" in UniProtKB|website=www.uniprot.org|access-date=2019-06-24}}</ref> Although numerous classification schemes have been proposed, the superfamily was classically divided into three main classes (A, B, and C) with no detectable shared [[sequence homology]] between classes.{{citation needed|date=April 2025}}

The largest class by far is class A, which accounts for nearly 85% of the GPCR genes. Of class&nbsp;A GPCRs, over half of these are predicted to encode [[olfactory receptor]]s, while the remaining receptors are [[ligand (biochemistry)|liganded]] by known [[endogenous]] [[chemical compound|compounds]] or are classified as [[orphan receptor]]s. Despite the lack of sequence homology between classes, all GPCRs have a common [[protein tertiary structure|structure]] and mechanism of [[signal transduction]]. The very large rhodopsin&nbsp;A group has been further subdivided into 19 subgroups ([[rhodopsin-like receptors#Classes|A1-A19]]).<ref>{{cite journal | vauthors = Joost P, Methner A | title = Phylogenetic analysis of 277 human G-protein-coupled receptors as a tool for the prediction of orphan receptor ligands | journal = Genome Biology | volume = 3 | issue = 11 | pages = RESEARCH0063 | date = October 2002 | article-number = research0063.1 | pmid = 12429062 | pmc = 133447 | doi = 10.1186/gb-2002-3-11-research0063 | doi-access = free }}</ref>

According to the classical A-F system, GPCRs can be grouped into six classes based on sequence homology and functional similarity:<ref>{{cite journal | vauthors = Attwood TK, Findlay JB | title = Fingerprinting G-protein-coupled receptors | journal = Protein Engineering | volume = 7 | issue = 2 | pages = 195–203 | date = February 1994 | pmid = 8170923 | doi = 10.1093/protein/7.2.195 }}</ref><ref>{{cite journal | vauthors = Kolakowski LF | title = GCRDb: a G-protein-coupled receptor database | journal = Receptors & Channels | volume = 2 | issue = 1 | pages = 1–7 | year = 1994 | pmid = 8081729 }}</ref><ref>{{cite journal | vauthors = Foord SM, Bonner TI, Neubig RR, Rosser EM, Pin JP, Davenport AP, Spedding M, Harmar AJ | title = International Union of Pharmacology. XLVI. G protein-coupled receptor list | journal = Pharmacological Reviews | volume = 57 | issue = 2 | pages = 279–88 | date = June 2005 | pmid = 15914470 | doi = 10.1124/pr.57.2.5 | s2cid = 34541683 }}</ref><ref>{{Cite web |url=https://www.ebi.ac.uk/interpro/ISearch?query=gpcr |title=InterPro |access-date=10 December 2007 |archive-date=21 February 2008 |archive-url=https://web.archive.org/web/20080221103146/https://www.ebi.ac.uk/interpro/ISearch?query=gpcr |url-status=live }}</ref>
* [[Class A GPCR|Class A]] (or 1) ([[Rhodopsin-like receptors|Rhodopsin-like]])
* [[Class B GPCR|Class B]] (or 2) ([[Secretin receptor family]])
* [[Class C GPCR|Class C]] (or 3) ([[Metabotropic glutamate receptor|Metabotropic glutamate]]/pheromone)
* [[Class D GPCR|Class D]] (or 4) ([[Fungal mating pheromone receptors]])
* [[Class E GPCR|Class E]] (or 5) ([[Cyclic AMP receptors]])
* [[Class F GPCR|Class F]] (or 6) ([[Frizzled]]/[[Smoothened]])

More recently, an alternative classification system called [[GRAFS]] ([[metabotropic glutamate receptor|Glutamate]], [[Rhodopsin]], [[adhesion G protein-coupled receptor|''Adhesion'']], [[Frizzled]]/[[taste receptor|Taste2]], [[secretin receptor|Secretin]]) has been proposed for vertebrate GPCRs.<ref name="pmid16753280"/>  They correspond to classical classes C, A, B2, F, and B.<ref name=pmid22238661/>

An early study based on available DNA sequence suggested that the human genome encodes roughly 750 G protein-coupled receptors,<ref>{{cite journal | vauthors = Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA | title = The G protein-coupled receptor repertoires of human and mouse | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 8 | pages = 4903–8 | date = April 2003 | pmid = 12679517 | pmc = 153653 | doi = 10.1073/pnas.0230374100 | bibcode = 2003PNAS..100.4903V | doi-access = free }}</ref> about 350 of which detect hormones, growth factors, and other endogenous ligands. Approximately 150 of the GPCRs found in the human genome have unknown functions.

Some web-servers<ref>{{cite journal | vauthors = Xiao X, Wang P, Chou KC | title = GPCR-CA: A cellular automaton image approach for predicting G-protein-coupled receptor functional classes | journal = Journal of Computational Chemistry | volume = 30 | issue = 9 | pages = 1414–23 | date = July 2009 | pmid = 19037861 | doi = 10.1002/jcc.21163 | s2cid = 813484 | url = https://www.jci-bioinfo.cn/GPCR-CA | archive-url = https://web.archive.org/web/20170409012210/https://jci-bioinfo.cn/GPCR-CA | archive-date = 2017-04-09 | url-access = subscription }}</ref> and bioinformatics prediction methods<ref name="pmid19364489">{{cite journal | vauthors = Qiu JD, Huang JH, Liang RP, Lu XQ | title = Prediction of G-protein-coupled receptor classes based on the concept of Chou's pseudo amino acid composition: an approach from discrete wavelet transform | journal = Analytical Biochemistry | volume = 390 | issue = 1 | pages = 68–73 | date = July 2009 | pmid = 19364489 | doi = 10.1016/j.ab.2009.04.009 }}</ref><ref name="pmid19594431">{{cite journal | vauthors = Gu Q, Ding YS, Zhang TL | title = Prediction of G-protein-coupled receptor classes in low homology using Chou's pseudo amino acid composition with approximate entropy and hydrophobicity patterns | journal = Protein and Peptide Letters | volume = 17 | issue = 5 | pages = 559–67 | date = May 2010 | pmid = 19594431 | doi = 10.2174/092986610791112693 }}</ref> have been used for predicting the classification of GPCRs according to their amino acid sequence alone, by means of the [[pseudo amino acid composition]] approach.

==Physiological roles==
GPCRs are involved in a wide variety of physiological processes. Some examples of their physiological roles include:
# The visual sense: The [[opsin]]s use a [[photoisomerization]] reaction to translate [[electromagnetic radiation]] into cellular signals. [[Rhodopsin]], for example, uses the conversion of [[Retinal|''11-cis''-retinal]] to [[Retinal|''all-trans''-retinal]] for this purpose.{{citation needed|date=April 2025}}
# The gustatory sense (taste): GPCRs in taste cells mediate release of [[gustducin]] in response to bitter-, umami- and sweet-tasting substances.{{citation needed|date=April 2025}}
# The sense of smell: Receptors of the [[olfactory epithelium]] bind odorants (olfactory receptors) and pheromones (vomeronasal receptors){{citation needed|date=April 2025}}
# Behavioral and mood regulation: G protein-coupled receptors in the [[mammal]]ian [[brain]] bind several different [[neurotransmitter]]s, including [[serotonin]], [[dopamine]], [[histamine]], [[noradrenaline]], and [[Gamma-aminobutyric acid|GABA]]. Notable exceptions include [[GABAA receptor|GABA<sub>A</sub> receptor]],<ref name="elifesciences.org">{{Cite journal |last1=Phulera |first1=Swastik |last2=Zhu |first2=Hongtao |last3=Yu |first3=Jie |last4=Claxton |first4=Derek P. |last5=Yoder |first5=Nate |last6=Yoshioka |first6=Craig |last7=Gouaux |first7=Eric |date=2018-07-25 |title=Cryo-EM structure of the benzodiazepine-sensitive α1β1γ2S tri-heteromeric GABA<sub>A</sub> receptor in complex with GABA |journal=eLife |language=en |volume=7 |article-number=e39383 |doi=10.7554/eLife.39383 |doi-access=free |issn=2050-084X |pmc=6086659 |pmid=30044221}}</ref> [[5-HT3 receptor|5-HT<sub>3</sub> serotonin receptor]]<ref name=Barnes>{{cite journal |vauthors =Barnes NM, Hales TG, Lummis SC, Peters JA |title=The 5-HT3 receptor--the relationship between structure and function |journal=Neuropharmacology |volume=56 |issue=1 |pages=273–284 |date=January 2009 |pmid=18761359 |pmc=6485434 |doi=10.1016/j.neuropharm.2008.08.003}}</ref> and [[glutamate receptor]]s ([[NMDAR]], [[AMPAR]] and [[kainate receptor]]),<ref name="pmid15242652">{{cite journal | vauthors = Debanne D, Daoudal G, Sourdet V, Russier M | title = Brain plasticity and ion channels | journal = Journal of Physiology, Paris | volume = 97 | issue = 4–6 | pages = 403–14 | year = 2003 | pmid = 15242652 | doi = 10.1016/j.jphysparis.2004.01.004 | s2cid = 19116187 }}</ref> which are ion channels.
# Regulation of [[immune system]] activity and [[inflammation]]: [[chemokine]] receptors bind ligands that mediate intercellular communication between cells of the immune system; receptors such as [[histamine receptor]]s bind [[inflammatory mediators]] and engage target cell types in the [[Inflammation|inflammatory response]]. GPCRs are also involved in immune-modulation, e. g. regulating interleukin induction<ref>{{cite journal | vauthors = Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL | title = Cannabinoid Receptor 2 (CB<sub>2</sub>) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes | journal = ACS Pharmacology & Translational Science | volume = 2 | issue = 6 | pages = 414–428 | date = December 2019 | pmid = 32259074 | doi = 10.1021/acsptsci.9b00049 | pmc = 7088898 | doi-access = free }}</ref> or suppressing [[Toll-like receptor|TLR]]-induced immune responses from T cells.<ref>{{cite journal | vauthors = Sharma N, Akhade AS, Qadri A | title = Sphingosine-1-phosphate suppresses TLR-induced CXCL8 secretion from human T cells | journal = Journal of Leukocyte Biology | volume = 93 | issue = 4 | pages = 521–8 | date = April 2013 | pmid = 23345392 | doi = 10.1189/jlb.0712328 | s2cid = 21897008 | doi-access =  }}</ref>
# Autonomic nervous system transmission: Both the [[sympathetic nervous system|sympathetic]] and [[parasympathetic nervous system|parasympathetic]] nervous systems are regulated by GPCR pathways. The involved receptors include [[adrenergic receptor]]s ([[Alpha-1 adrenergic receptor|α<sub>1</sub>]], [[Alpha-2 adrenergic receptor|α<sub>2</sub>]], [[Beta-1 adrenergic receptor|β<sub>1</sub>]], [[Beta-2 adrenergic receptor|β<sub>2</sub>]] and [[Beta-3 adrenergic receptor|β<sub>3</sub>]], of which β<sub>2</sub> is notable for being the first GPCR to have the crystal structure determined) for the sympathetic nervous system and [[muscarinic acetylcholine receptor]]s for the parasympathetic nervous system. Adrenergic receptor ligands are known to modulate blood pressure and heart rate, while muscarinic antagonists produce a host of symptoms such as pupil dilation, urinary retention, constipation and dry mouth that are directly related to inhibition of the parasympathetic nervous system.<ref name=":1">{{Cite book|title=The adrenergic receptors in the 21st century|last=Perez|first=Dianne M.|publisher=Humana Press|year=2006|isbn=978-1588294234|location=Totowa, New Jersey|pages=54, 129–134|lccn=2005008529|oclc=58729119}}</ref><ref name="Purves" >{{cite book | author = Purves, Dale, George J. Augustine, David Fitzpatrick, William C. Hall, Anthony-Samuel LaMantia, James O. McNamara, and Leonard E. White | title = Neuroscience. 4th ed. | publisher = Sinauer Associates | pages = 122–6 | year = 2008 | isbn = 978-0-87893-697-7}}</ref>
# Cell density sensing: A novel GPCR role in regulating cell density sensing.
# Homeostasis modulation (e.g., water balance).<ref name="pmid21802439">{{cite journal | vauthors = Hazell GG, Hindmarch CC, Pope GR, Roper JA, Lightman SL, Murphy D, O'Carroll AM, Lolait SJ | title = G protein-coupled receptors in the hypothalamic paraventricular and supraoptic nuclei--serpentine gateways to neuroendocrine homeostasis | journal = Frontiers in Neuroendocrinology | volume = 33 | issue = 1 | pages = 45–66 | date = January 2012 | pmid = 21802439 | pmc = 3336209 | doi = 10.1016/j.yfrne.2011.07.002 }}</ref>
# Involved in growth and [[metastasis]] of some types of [[tumor]]s.<ref>{{cite journal | vauthors = Dorsam RT, Gutkind JS | title = G-protein-coupled receptors and cancer | journal = Nature Reviews. Cancer | volume = 7 | issue = 2 | pages = 79–94 | date = February 2007 | pmid = 17251915 | doi = 10.1038/nrc2069 | s2cid = 10996598 }}</ref>
# Used in the endocrine system for peptide and amino-acid derivative hormones that bind to GCPRs on the cell membrane of a target cell. This activates cAMP, which in turn activates several kinases, allowing for a cellular response, such as transcription.

==Receptor structure==

GPCRs are [[integral membrane protein]]s that possess seven membrane-spanning domains or [[transmembrane helix|transmembrane helices]].<ref name="pmid 23407534">{{cite journal | vauthors = Venkatakrishnan AJ, Deupi X, Lebon G, Tate CG, Schertler GF, Babu MM | title = Molecular signatures of G-protein-coupled receptors | journal = Nature | volume = 494 | issue = 7436 | pages = 185–94 | date = February 2013 | pmid = 23407534 | doi = 10.1038/nature11896 | bibcode = 2013Natur.494..185V | s2cid = 4423750 }}</ref><ref name="pmid24359917">{{cite journal | vauthors = Hollenstein K, de Graaf C, Bortolato A, Wang MW, Marshall FH, Stevens RC | title = Insights into the structure of class B GPCRs | journal = Trends in Pharmacological Sciences | volume = 35 | issue = 1 | pages = 12–22 | date = January 2014 | pmid = 24359917 | pmc = 3931419 | doi = 10.1016/j.tips.2013.11.001 }}</ref> The extracellular parts of the receptor can be [[glycosylation|glycosylated]]. These extracellular loops also contain two highly conserved [[cysteine]] residues that form [[disulfide bond]]s to stabilize the receptor structure. Some seven-transmembrane helix proteins ([[channelrhodopsin]]) that resemble GPCRs may contain ion channels, within their protein.{{citation needed|date=April 2025}}

In 2000, the first crystal structure of a mammalian GPCR, that of bovine [[rhodopsin]] ({{PDB2|1F88}}), was solved.<ref name="pmid10926528">{{cite journal | vauthors = Palczewski K, Kumasaka T, Hori T, Behnke CA, Motoshima H, Fox BA, Le Trong I, Teller DC, Okada T, Stenkamp RE, Yamamoto M, Miyano M | title = Crystal structure of rhodopsin: A G protein-coupled receptor | journal = Science | volume = 289 | issue = 5480 | pages = 739–45 | date = August 2000 | pmid = 10926528 | doi = 10.1126/science.289.5480.739 | bibcode = 2000Sci...289..739P | citeseerx = 10.1.1.1012.2275 }}</ref> In 2007, the first structure of a human GPCR was solved <ref name="Rasmussen_2007">{{cite journal | vauthors = Rasmussen SG, Choi HJ, Rosenbaum DM, Kobilka TS, Thian FS, Edwards PC, Burghammer M, Ratnala VR, Sanishvili R, Fischetti RF, Schertler GF, Weis WI, Kobilka BK | title = Crystal structure of the human beta2 adrenergic G-protein-coupled receptor | journal = Nature | volume = 450 | issue = 7168 | pages = 383–7 | date = November 2007 | pmid = 17952055 | doi = 10.1038/nature06325 | bibcode = 2007Natur.450..383R | s2cid = 4407117 }}</ref><ref name="Cherezov_2007">{{cite journal | vauthors = Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC | title = High-resolution crystal structure of an engineered human beta2-adrenergic G protein-coupled receptor | journal = Science | volume = 318 | issue = 5854 | pages = 1258–65 | date = November 2007 | pmid = 17962520 | pmc = 2583103 | doi = 10.1126/science.1150577 | bibcode = 2007Sci...318.1258C }}</ref><ref name="Rosenbaum_2007">{{cite journal | vauthors = Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK | s2cid = 1559802 | title = GPCR engineering yields high-resolution structural insights into beta2-adrenergic receptor function | journal = Science | volume = 318 | issue = 5854 | pages = 1266–73 | date = November 2007 | pmid = 17962519 | doi = 10.1126/science.1150609 | bibcode = 2007Sci...318.1266R | doi-access = free }}</ref> This human [[beta-2 adrenergic receptor|β<sub>2</sub>-adrenergic receptor]] GPCR structure proved highly similar to the bovine rhodopsin. The structures of activated or agonist-bound GPCRs have also been determined.<ref name="pmid21228869">{{cite journal | vauthors = Rasmussen SG, Choi HJ, Fung JJ, Pardon E, Casarosa P, Chae PS, Devree BT, Rosenbaum DM, Thian FS, Kobilka TS, Schnapp A, Konetzki I, Sunahara RK, Gellman SH, Pautsch A, Steyaert J, Weis WI, Kobilka BK | title = Structure of a nanobody-stabilized active state of the β(2) adrenoceptor | journal = Nature | volume = 469 | issue = 7329 | pages = 175–80 | date = January 2011 | pmid = 21228869 | pmc = 3058308 | doi = 10.1038/nature09648 | bibcode = 2011Natur.469..175R }}</ref><ref name="pmid21228876">{{cite journal | vauthors = Rosenbaum DM, Zhang C, Lyons JA, Holl R, Aragao D, Arlow DH, Rasmussen SG, Choi HJ, Devree BT, Sunahara RK, Chae PS, Gellman SH, Dror RO, Shaw DE, Weis WI, Caffrey M, Gmeiner P, Kobilka BK | title = Structure and function of an irreversible agonist-β(2) adrenoceptor complex | journal = Nature | volume = 469 | issue = 7329 | pages = 236–40 | date = January 2011 | pmid = 21228876 | pmc = 3074335 | doi = 10.1038/nature09665 | bibcode = 2011Natur.469..236R }}</ref><ref name="pmid21228877">{{cite journal | vauthors = Warne T, Moukhametzianov R, Baker JG, Nehmé R, Edwards PC, Leslie AG, Schertler GF, Tate CG | title = The structural basis for agonist and partial agonist action on a β(1)-adrenergic receptor | journal = Nature | volume = 469 | issue = 7329 | pages = 241–4 | date = January 2011 | pmid = 21228877 | pmc = 3023143 | doi = 10.1038/nature09746 | bibcode = 2011Natur.469..241W }}</ref><ref name="pmid21393508">{{cite journal | vauthors = Xu F, Wu H, Katritch V, Han GW, Jacobson KA, Gao ZG, Cherezov V, Stevens RC | title = Structure of an agonist-bound human A2A adenosine receptor | journal = Science | volume = 332 | issue = 6027 | pages = 322–7 | date = April 2011 | pmid = 21393508 | pmc = 3086811 | doi = 10.1126/science.1202793 | bibcode = 2011Sci...332..322X }}</ref> These structures indicate how ligand binding at the extracellular side of a receptor leads to conformational changes in the cytoplasmic side of the receptor. The biggest change is an outward movement of the cytoplasmic part of the 5th and 6th transmembrane helix (TM5 and TM6). The structure of activated beta-2 adrenergic receptor in complex with G<sub>s</sub> confirmed that the Gα binds to a cavity created by this movement.<ref name="pmid21772288">{{cite journal | vauthors = Rasmussen SG, DeVree BT, Zou Y, Kruse AC, Chung KY, Kobilka TS, Thian FS, Chae PS, Pardon E, Calinski D, Mathiesen JM, Shah ST, Lyons JA, Caffrey M, Gellman SH, Steyaert J, Skiniotis G, Weis WI, Sunahara RK, Kobilka BK | title = Crystal structure of the β2 adrenergic receptor-Gs protein complex | journal = Nature | volume = 477 | issue = 7366 | pages = 549–55 | date = July 2011 | pmid = 21772288 | pmc = 3184188 | doi = 10.1038/nature10361 | bibcode = 2011Natur.477..549R }}</ref>

GPCRs exhibit a similar structure to some other proteins with seven [[transmembrane domain]]s, such as [[microbial rhodopsin]]s and adiponectin receptors 1 and 2 ([[ADIPOR1]] and [[ADIPOR2]]). However, these 7TMH (7-transmembrane helices) receptors and channels do not associate with [[G protein]]s. In addition, ADIPOR1 and ADIPOR2 are oriented oppositely to GPCRs in the membrane (i.e. GPCRs usually have an extracellular N-terminus, cytoplasmic C-terminus, whereas ADIPORs are inverted).<ref name="pmid12802337">{{cite journal | vauthors = Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T | title = Cloning of adiponectin receptors that mediate antidiabetic metabolic effects | journal = Nature | volume = 423 | issue = 6941 | pages = 762–9 | date = June 2003 | pmid = 12802337 | doi = 10.1038/nature01705 | bibcode = 2003Natur.423..762Y | s2cid = 52860797 }}</ref>

==Structure–function relationships==

[[File:GPCR in membrane.png|right|thumb|500px|Two-dimensional schematic of a generic GPCR set in a [[lipid raft]]. Click the image for higher resolution to see details regarding the locations of important structures.]]
In terms of structure, GPCRs are characterized by an extracellular N-terminus, followed by seven [[transmembrane domain|transmembrane]] (7-TM) [[alpha helix|α-helices]] (TM-1 to TM-7) connected by three intracellular (IL-1 to IL-3) and three extracellular loops (EL-1 to EL-3), and finally an intracellular C-terminus. The GPCR arranges itself into a [[protein tertiary structure|tertiary structure]] resembling a barrel, with the seven transmembrane helices forming a cavity within the plasma membrane that serves a [[ligand (biochemistry)|ligand]]-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is the case for bulkier ligands (e.g., [[protein]]s or large [[peptide]]s), which instead interact with the extracellular loops, or, as illustrated by the class C [[metabotropic glutamate receptors]] (mGluRs), the N-terminal tail. The class C GPCRs are distinguished by their large N-terminal tail, which also contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes a conformational change that leads to its interaction with the residues of the extracellular loops and TM domains. The eventual effect of all three types of [[agonist]]-induced activation is a change in the relative orientations of the TM helices (likened to a twisting motion) leading to a wider intracellular surface and "revelation" of residues of the intracellular helices and TM domains crucial to signal transduction function (i.e., G-protein coupling). [[Inverse agonist]]s and [[receptor antagonist|antagonist]]s may also bind to a number of different sites, but the eventual effect must be prevention of this TM helix reorientation.<ref name="Trzaskowski2012" />

The structure of the N- and C-terminal tails of GPCRs may also serve important functions beyond ligand-binding. For example, The C-terminus of M<sub>3</sub> muscarinic receptors is sufficient, and the six-amino-acid polybasic (KKKRRK) domain in the C-terminus is necessary for its preassembly with G<sub>q</sub> proteins.<ref name=" pmid=21873996 ">{{cite journal | vauthors = Qin K, Dong C, Wu G, Lambert NA | title = Inactive-state preassembly of G(q)-coupled receptors and G(q) heterotrimers | journal = Nature Chemical Biology | volume = 7 | issue = 10 | pages = 740–7 | date = August 2011 | pmid = 21873996 | pmc = 3177959 | doi = 10.1038/nchembio.642 }}</ref> In particular, the C-terminus often contains [[serine]] (Ser) or [[threonine]] (Thr) residues that, when [[phosphorylation|phosphorylated]], increase the [[affinity (pharmacology)|affinity]] of the intracellular surface for the binding of scaffolding proteins called β-[[arrestin]]s (β-arr).<ref name="pmid2163110">{{cite journal | vauthors = Lohse MJ, Benovic JL, Codina J, Caron MG, Lefkowitz RJ | title = beta-Arrestin: a protein that regulates beta-adrenergic receptor function | journal = Science | volume = 248 | issue = 4962 | pages = 1547–50 | date = June 1990 | pmid = 2163110 | doi = 10.1126/science.2163110 | bibcode = 1990Sci...248.1547L }}</ref> Once bound, β-arrestins both [[sterically]] prevent G-protein coupling and may recruit other proteins, leading to the creation of signaling complexes involved in extracellular-signal regulated kinase ([[extracellular signal-regulated kinases|ERK]]) pathway activation or receptor [[endocytosis]] (internalization). As the phosphorylation of these Ser and Thr residues often occurs as a result of GPCR activation, the β-arr-mediated G-protein-decoupling and internalization of GPCRs are important mechanisms of [[desensitization (medicine)|desensitization]].<ref name="pmid11861753">{{cite journal | vauthors = Luttrell LM, Lefkowitz RJ | title = The role of beta-arrestins in the termination and transduction of G-protein-coupled receptor signals | journal = Journal of Cell Science | volume = 115 | issue = Pt 3 | pages = 455–65 | date = February 2002 | doi = 10.1242/jcs.115.3.455 | pmid = 11861753 | hdl = 10161/7805 | hdl-access = free }}</ref> In addition, internalized "mega-complexes" consisting of a single GPCR, β-arr(in the tail conformation),<ref name="pmid28223524">{{cite journal | vauthors = Cahill TJ, Thomsen AR, Tarrasch JT, Plouffe B, Nguyen AH, Yang F, Huang LY, Kahsai AW, Bassoni DL, Gavino BJ, Lamerdin JE, Triest S, Shukla AK, Berger B, Little J, Antar A, Blanc A, Qu CX, Chen X, Kawakami K, Inoue A, Aoki J, Steyaert J, Sun JP, Bouvier M, Skiniotis G, Lefkowitz RJ | title = Distinct conformations of GPCR-β-arrestin complexes mediate desensitization, signaling, and endocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 114 | issue = 10 | pages = 2562–2567 | date = March 2017 | pmid = 28223524 | pmc = 5347553 | doi = 10.1073/pnas.1701529114 | bibcode = 2017PNAS..114.2562C | doi-access = free }}</ref><ref name="pmid27827372">{{cite journal | vauthors = Kumari P, Srivastava A, Banerjee R, Ghosh E, Gupta P, Ranjan R, Chen X, Gupta B, Gupta C, Jaiman D, Shukla AK | title = Functional competence of a partially engaged GPCR-β-arrestin complex | journal = Nature Communications | volume = 7 | article-number = 13416 | date = November 2016 | pmid = 27827372 | pmc = 5105198 | doi = 10.1038/ncomms13416 | bibcode = 2016NatCo...713416K }}</ref> and heterotrimeric G protein exist and may account for protein signaling from endosomes.<ref name="pmid27499021">{{cite journal | vauthors = Thomsen AR, Plouffe B, Cahill TJ, Shukla AK, Tarrasch JT, Dosey AM, Kahsai AW, Strachan RT, Pani B, Mahoney JP, Huang L, Breton B, Heydenreich FM, Sunahara RK, Skiniotis G, Bouvier M, Lefkowitz RJ | title = GPCR-G Protein-β-Arrestin Super-Complex Mediates Sustained G Protein Signaling | journal = Cell | volume = 166 | issue = 4 | pages = 907–919 | date = August 2016 | pmid = 27499021 | pmc = 5418658 | doi = 10.1016/j.cell.2016.07.004 }}</ref><ref name="pmid31740855">{{cite journal | vauthors = Nguyen AH, Thomsen AR, Cahill TJ, Huang R, Huang LY, Marcink T, Clarke OB, Heissel S, Masoudi A, Ben-Hail D, Samaan F, Dandey VP, Tan YZ, Hong C, Mahoney JP, Triest S, Little J, Chen X, Sunahara R, Steyaert J, Molina H, Yu Z, des Georges A, Lefkowitz RJ | title = Structure of an endosomal signaling GPCR-G protein-β-arrestin megacomplex | journal = Nature Structural & Molecular Biology | volume = 26 | issue = 12 | pages = 1123–1131 | date = December 2019 | pmid = 31740855 | pmc = 7108872 | doi = 10.1038/s41594-019-0330-y }}</ref>

A final common structural theme among GPCRs is [[palmitoylation]] of one or more sites of the C-terminal tail or the intracellular loops. Palmitoylation is the covalent modification of [[cysteine]] (Cys) residues via addition of hydrophobic [[acyl group]]s, and has the effect of targeting the receptor to [[cholesterol]]- and [[sphingolipid]]-rich microdomains of the plasma membrane called [[lipid raft]]s. As many of the downstream transducer and effector molecules of GPCRs (including those involved in [[negative feedback]] pathways) are also targeted to lipid rafts, this has the effect of facilitating rapid receptor signaling.{{citation needed|date=April 2025}}

GPCRs respond to extracellular signals mediated by a huge diversity of agonists, ranging from proteins to [[biogenic amines]] to [[protons]], but all transduce this signal via a mechanism of G-protein coupling. This is made possible by a [[guanine]]-nucleotide exchange factor ([[guanine nucleotide exchange factor|GEF]]) domain primarily formed by a combination of IL-2 and IL-3 along with adjacent residues of the associated TM helices.{{citation needed|date=April 2025}}

==Mechanism==
[[File:GPCR activation.jpg|right|thumb|400px|Cartoon depicting the basic concept of GPCR conformational activation. Ligand binding disrupts an ionic lock between the E/DRY motif of TM-3 and acidic residues of TM-6. As a result, the GPCR reorganizes to allow activation of G-alpha proteins. The "side perspective" is a view from above and to the side of the GPCR as it is set in the plasma membrane (the membrane lipids have been omitted for clarity). The incorrectly labelled "intracellular perspective" shows an extracellular view looking down at the plasma membrane from outside the cell.<ref name="pmid20019124">{{cite journal | vauthors = Millar RP, Newton CL | title = The year in G protein-coupled receptor research | journal = Molecular Endocrinology | volume = 24 | issue = 1 | pages = 261–74 | date = January 2010 | pmid = 20019124 | pmc = 5428143 | doi = 10.1210/me.2009-0473 }}</ref>]]

The G protein-coupled receptor is activated by an external signal in the form of a ligand or other signal mediator. This creates a conformational change in the receptor, causing activation of a [[G protein]]. Further effect depends on the type of G protein. G proteins are subsequently inactivated by GTPase activating proteins, known as [[regulator of G protein signaling|RGS proteins]].{{citation needed|date=April 2025}}

===Ligand binding===
GPCRs include one or more receptors for the following ligands:
sensory signal mediators (e.g., light and [[olfactory]] stimulatory molecules);
[[adenosine]], [[bombesin]], [[bradykinin]], [[endothelin]], γ-aminobutyric acid ([[gamma-aminobutyric acid|GABA]]), hepatocyte growth factor ([[hepatocyte growth factor|HGF]]), [[melanocortin]]s, [[neuropeptide Y]], [[opioid]] peptides, [[opsin]]s, [[somatostatin]], [[growth hormone|GH]], [[tachykinins]], members of the [[vasoactive intestinal peptide]] family, and [[vasopressin]];
[[biogenic amine]]s (e.g., [[dopamine]], [[epinephrine]], [[norepinephrine]], [[histamine]], [[serotonin]], and [[melatonin]]);
[[glutamate]] ([[metabotropic]] effect);
[[glucagon]];
[[acetylcholine]] ([[muscarinic]] effect);
[[chemokines]];
[[lipid]] mediators of [[inflammation]] (e.g., [[prostaglandins]], [[prostanoid]]s, [[platelet-activating factor]], and [[leukotrienes]]);
peptide hormones (e.g., [[calcitonin]], C5a [[anaphylatoxin]], [[follicle-stimulating hormone]] [FSH], [[gonadotropin-releasing hormone]] [GnRH], [[neurokinin]], [[thyrotropin-releasing hormone]] [TRH], and [[oxytocin]]);
and [[endocannabinoid]]s.

GPCRs that act as receptors for stimuli that have not yet been identified are known as [[orphan receptor]]s.{{citation needed|date=April 2025}}

However, in contrast to other types of receptors that have been studied, wherein ligands bind externally to the membrane, the [[ligand (biochemistry)|ligand]]s of GPCRs typically bind within the transmembrane domain. However, [[protease-activated receptor]]s are activated by cleavage of part of their extracellular domain.<ref name="pmid12970120">{{cite journal | vauthors = Brass LF | s2cid = 22279536 | title = Thrombin and platelet activation | journal = Chest | volume = 124 | issue = 3 Suppl | pages = 18S–25S | date = September 2003 | pmid = 12970120 | doi = 10.1378/chest.124.3_suppl.18S }}</ref>

=== Conformational change ===

[[File:Beta2Receptor-with-Gs.png|right|thumb|300px|Crystal structure of activated beta-2 adrenergic receptor in complex with G<sub>s</sub>([[w:Protein Data Bank|PDB]] entry [https://web.archive.org/web/20180128134132/https://www.rcsb.org/structure/3SN6 3SN6]). The receptor is colored red, Gα green, Gβ cyan, and Gγ yellow. The C-terminus of Gα is located in a cavity created by an outward movement of the cytoplasmic parts of TM5 and 6.]]

The [[signal transduction|transduction of the signal]] through the membrane by the receptor is not completely understood. It is known that in the inactive state, the GPCR is bound to a [[heterotrimeric G protein]] complex. Binding of an agonist to the GPCR results in a [[conformational change]] in the receptor that is transmitted to the bound G<sub>α</sub> subunit of the heterotrimeric G protein via [[protein dynamics#Global flexibility: multiple domains|protein domain dynamics]]. The activated G<sub>α</sub> subunit exchanges [[guanosine triphosphate|GTP]] in place of [[guanosine diphosphate|GDP]] which in turn triggers the dissociation of G<sub>α</sub> subunit from the G<sub>βγ</sub> dimer and from the receptor. The dissociated G<sub>α</sub> and G<sub>βγ</sub> subunits interact with other intracellular proteins to continue the signal transduction cascade while the freed GPCR is able to rebind to another heterotrimeric G protein to form a new complex that is ready to initiate another round of signal transduction.<ref name="pmid17095603">{{cite journal | vauthors = Digby GJ, Lober RM, Sethi PR, Lambert NA | title = Some G protein heterotrimers physically dissociate in living cells | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 47 | pages = 17789–94 | date = November 2006 | pmid = 17095603 | pmc = 1693825 | doi = 10.1073/pnas.0607116103 | bibcode = 2006PNAS..10317789D | doi-access = free }}</ref>

It is believed that a receptor molecule exists in a conformational [[dynamic equilibrium|equilibrium]] between active and inactive biophysical states.<ref>{{cite journal |vauthors=Rubenstein LA, Lanzara RG |title=Activation of G protein-coupled receptors entails cysteine modulation of agonist binding |journal= Journal of Molecular Structure: Theochem|year=1998 |volume=430 |pages=57–71 |url=https://cogprints.org/4095/ |doi=10.1016/S0166-1280(98)90217-2 |access-date=14 January 2006 |archive-date=16 May 2011 |archive-url=https://web.archive.org/web/20110516061030/https://cogprints.org/4095/ |url-status=live |url-access=subscription }}</ref> The binding of ligands to the receptor may shift the equilibrium toward the active receptor states. Three types of ligands exist: Agonists are ligands that shift the equilibrium in favour of active states; [[inverse agonist]]s are ligands that shift the equilibrium in favour of inactive states; and neutral antagonists are ligands that do not affect the equilibrium. It is not yet known how exactly the active and inactive states differ from each other.{{citation needed|date=April 2025}}

===G-protein activation/deactivation cycle===
[[File:GPCR cycle.jpg|thumb|500px|Cartoon depicting the heterotrimeric G-protein activation/deactivation cycle in the context of GPCR signaling]]
{{See also|G protein}}
When the receptor is inactive, the [[guanine nucleotide exchange factor|GEF]] domain may be bound to an also inactive α-subunit of a [[heterotrimeric G-protein]]. These "G-proteins" are a [[protein trimer|trimer]] of α, β, and γ subunits (known as Gα, Gβ, and Gγ, respectively) that is rendered inactive when reversibly bound to [[Guanosine diphosphate]] (GDP) (or, alternatively, no guanine nucleotide) but active when bound to [[guanosine triphosphate]] (GTP). Upon receptor activation, the GEF domain, in turn, [[allosterically]] activates the G-protein by facilitating the exchange of a molecule of GDP for GTP at the G-protein's α-subunit. The cell maintains a 10:1 ratio of cytosolic GTP:GDP so exchange for GTP is ensured. At this point, the subunits of the G-protein dissociate from the receptor, as well as each other, to yield a Gα-GTP [[monomer]] and a tightly interacting [[G beta-gamma complex|Gβγ dimer]], which are now free to modulate the activity of other intracellular proteins. The extent to which they may [[diffuse]], however, is limited due to the [[palmitoylation]] of Gα and the presence of an [[isoprenoid]] moiety that has been [[covalent bond|covalently]] added to the C-termini of Gγ.{{citation needed|date=April 2025}}

Because Gα also has slow [[GTP-ase|GTP→GDP hydrolysis]] capability, the inactive form of the α-subunit (Gα-GDP) is eventually regenerated, thus allowing reassociation with a Gβγ dimer to form the "resting" G-protein, which can again bind to a GPCR and await activation. The rate of GTP hydrolysis is often accelerated due to the actions of another family of allosteric modulating proteins called [[regulator of G protein signaling|regulators of G-protein signaling]], or RGS proteins, which are a type of [[GTPase-activating protein]], or GAP. In fact, many of the primary [[Effector (biology)|effector]] proteins (e.g., [[adenylate cyclase]]s) that become activated/inactivated upon interaction with Gα-GTP also have GAP activity. Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.{{citation needed|date=April 2025}}

===Crosstalk===
[[File:GPCR and itegrin signaling diagram.png|thumb|Proposed downstream interactions between [[integrin]] signaling and GPCRs. Integrins are shown elevating Ca<sup>2+</sup> and phosphorylating FAK, which is weakening GPCR signaling.]]
GPCRs downstream signals have been shown to possibly interact with [[integrin]] signals, such as [[PTK2|FAK]].<ref>{{cite journal | vauthors = Teoh CM, Tam JK, Tran T | title = Integrin and GPCR Crosstalk in the Regulation of ASM Contraction Signaling in Asthma | journal = Journal of Allergy | volume = 2012 | article-number = 341282 | year = 2012 | pmid = 23056062 | pmc = 3465959 | doi = 10.1155/2012/341282 | doi-access = free }}</ref> Integrin signaling will phosphorylate FAK, which can then decrease GPCR G<sub>αs</sub> activity.

==Signaling==

[[File:GPCR mechanism.png|right|thumb|300px|G-protein-coupled receptor mechanism]]
If a receptor in an active state encounters a [[G protein]], it may activate it. Some evidence suggests that receptors and G proteins are actually pre-coupled.<ref name=" pmid=21873996 "/> For example, binding of G proteins to receptors affects the receptor's affinity for ligands. Activated G proteins are bound to [[guanosine triphosphate|GTP]].

Further signal transduction depends on the type of G protein. The enzyme [[adenylate cyclase]] is an example of a cellular protein that can be regulated by a G protein, in this case the G protein [[Gs alpha subunit|G<sub>s</sub>]]. Adenylate cyclase activity is activated when it binds to a subunit of the activated G protein. Activation of adenylate cyclase ends when the G protein returns to the [[guanosine diphosphate|GDP]]-bound state.

Adenylate cyclases (of which 9 membrane-bound and one cytosolic forms are known in humans) may also be activated or inhibited in other ways (e.g., Ca2+/[[calmodulin]] binding), which can modify the activity of these enzymes in an additive or synergistic fashion along with the G proteins.

The signaling pathways activated through a GPCR are limited by the [[protein primary structure|primary sequence]] and [[tertiary structure]] of the GPCR itself but ultimately determined by the particular [[protein conformation|conformation]] stabilized by a particular [[ligand (biochemistry)|ligand]], as well as the availability of [[transducer]] molecules. Currently, GPCRs are considered to utilize two primary types of transducers: [[G-proteins]] and [[arrestin|β-arrestins]]. Because β-arr's have high [[affinity (pharmacology)|affinity]] only to the [[phosphorylated]] form of most GPCRs (see above or below), the majority of signaling is ultimately dependent upon G-protein activation. However, the possibility for interaction does allow for G-protein-independent signaling to occur.

===G-protein-dependent signaling===

There are three main G-protein-mediated signaling pathways, mediated by four [[class (biology)|sub-classes]] of G-proteins distinguished from each other by [[sequence homology]] ([[Gαs|G<sub>αs</sub>]], [[Gαi|G<sub>αi/o</sub>]], [[Gαq|G<sub>αq/11</sub>]], and [[G12/G13 alpha subunits|G<sub>α12/13</sub>]]). Each sub-class of G-protein consists of multiple proteins, each the product of multiple [[genes]] or [[splice variant|splice variations]] that may imbue them with differences ranging from subtle to distinct with regard to signaling properties, but in general they appear reasonably grouped into four classes. Because the signal transducing properties of the various possible [[G beta-gamma complex|βγ combinations]] do not appear to radically differ from one another, these classes are defined according to the isoform of their α-subunit.<ref name="Wettschureck_2005"/>{{rp|1163}}

While most GPCRs are capable of activating more than one Gα-subtype, they also show a preference for one subtype over another. When the subtype activated depends on the ligand that is bound to the GPCR, this is called [[functional selectivity]] (also known as agonist-directed trafficking, or conformation-specific agonism). However, the binding of any single particular [[agonist]] may also initiate activation of multiple different G-proteins, as it may be capable of stabilizing more than one conformation of the GPCR's [[guanine nucleotide exchange factor|GEF]] domain, even over the course of a single interaction. In addition, a conformation that preferably activates one [[isoform]] of Gα may activate another if the preferred is less available. Furthermore, [[feedback]] pathways may result in [[post-translational modification|receptor modifications]] (e.g., phosphorylation) that alter the G-protein preference. Regardless of these various nuances, the GPCR's preferred coupling partner is usually defined according to the G-protein most obviously activated by the [[endogenous]] ligand under most [[physiological]] or [[experimental]] conditions.

====Gα signaling====

# The effector of both the G<sub>αs</sub> and G<sub>αi/o</sub> pathways is the [[cyclic amp|cyclic-adenosine monophosphate]] (cAMP)-generating enzyme [[adenylyl cyclase|adenylate cyclase]], or AC. While there are ten different AC gene products in mammals, each with subtle differences in [[tissue (biology)|tissue]] distribution or function, all [[catalyze]] the conversion of [[cytosolic]] [[adenosine triphosphate]] (ATP) to cAMP, and all are directly stimulated by G-proteins of the G<sub>αs</sub> class. In contrast, however, interaction with Gα subunits of the G<sub>αi/o</sub> type inhibits AC from generating cAMP. Thus, a GPCR coupled to G<sub>αs</sub> counteracts the actions of a GPCR coupled to G<sub>αi/o</sub>, and vice versa. The level of cytosolic cAMP may then determine the activity of various [[cyclic nucleotide-gated ion channel|ion channels]] as well as members of the [[Serine/threonine-specific protein kinase|ser/thr-specific]] [[protein kinase A|protein kinase&nbsp;A]] (PKA) family. Thus cAMP is considered a [[second messenger system|second messenger]] and PKA a secondary [[effector (biology)|effector]].
# The effector of the G<sub>αq/11</sub> pathway is [[phospholipase C|phospholipase C-β]] (PLCβ), which catalyzes the cleavage of membrane-bound [[phosphatidylinositol 4,5-bisphosphate]] (PIP2) into the second messengers [[inositol trisphosphate|inositol (1,4,5) trisphosphate]] (IP3) and [[diglyceride|diacylglycerol]] (DAG). IP3 acts on [[inositol trisphosphate receptor|IP3 receptors]] found in the membrane of the [[endoplasmic reticulum]] (ER) to elicit [[Ca2+|Ca<sup>2+</sup>]] release from the ER, while DAG diffuses along the [[plasma membrane]] where it may activate any membrane localized forms of a second ser/thr kinase called [[protein kinase C]] (PKC). Since many isoforms of PKC are also activated by increases in intracellular Ca<sup>2+</sup>, both these pathways can also converge on each other to signal through the same secondary effector. Elevated intracellular Ca<sup>2+</sup> also binds and [[allosterically]] activates proteins called [[calmodulin]]s, which in turn tosolic [[small GTPase]], [[Rho family of GTPases|Rho]]. Once bound to GTP, Rho can then go on to activate various proteins responsible for [[cytoskeleton]] regulation such as [[Rho-associated protein kinase|Rho-kinase]] (ROCK). Most GPCRs that couple to G<sub>α12/13</sub> also couple to other sub-classes, often G<sub>αq/11</sub>.

====Gβγ signaling====

The above descriptions ignore the effects of [[G beta-gamma complex|Gβγ]]–signalling, which can also be important, in particular in the case of activated G<sub>αi/o</sub>-coupled GPCRs. The primary effectors of Gβγ are various ion channels, such as [[G protein-coupled inwardly-rectifying potassium channel|G-protein-regulated inwardly rectifying K<sup>+</sup> channels]] (GIRKs), [[P-type calcium channel|P]]/[[Q-type calcium channel|Q]]- and [[N-type calcium channel|N-]]type [[voltage-dependent calcium channel|voltage-gated Ca<sup>2+</sup> channels]], as well as some isoforms of AC and PLC, along with some [[PI3K|phosphoinositide-3-kinase]] (PI3K) isoforms.

===G-protein-independent signaling===

Although they are classically thought of working only together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteins may play functional roles independent of GPCRs. GPCRs may signal independently through many proteins already mentioned for their roles in G-protein-dependent signaling such as [[arrestin|β-arrs]], [[G protein-coupled receptor kinase|GRKs]], and [[Src (gene)|Srcs]]. Such signaling has been shown to be physiologically relevant, for example, [[arrestin|β-arrestin]] signaling mediated by the chemokine receptor [[CXCR3]] was necessary for full efficacy chemotaxis of activated T cells.<ref>{{cite journal | vauthors = Smith JS, Nicholson LT, Suwanpradid J, Glenn RA, Knape NM, Alagesan P, Gundry JN, Wehrman TS, Atwater AR, Gunn MD, MacLeod AS, Rajagopal S | title = Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation | journal = Science Signaling | volume = 11 | issue = 555 | article-number = eaaq1075 | date = November 2018 | pmid = 30401786 | pmc = 6329291 | doi = 10.1126/scisignal.aaq1075 }}</ref> In addition, further scaffolding proteins involved in [[subcellular localization]] of GPCRs (e.g., [[PDZ (biology)|PDZ-domain]]-containing proteins) may also act as signal transducers. Most often the effector is a member of the [[MAPK]] family.

====Examples====

In the late 1990s, evidence began accumulating to suggest that some GPCRs are able to signal without G proteins. The [[MAPK1|ERK2]] mitogen-activated protein kinase, a key signal transduction mediator downstream of receptor activation in many pathways, has been shown to be activated in response to cAMP-mediated receptor activation in the [[slime mold]] [[Dictyostelium discoideum|''D. discoideum'']] despite the absence of the associated G protein α- and β-subunits.<ref>{{cite journal | vauthors = Kim JY, Haastert PV, Devreotes PN | title = Social senses: G-protein-coupled receptor signaling pathways in Dictyostelium discoideum | journal = Chemistry & Biology | volume = 3 | issue = 4 | pages = 239–43 | date = April 1996 | pmid = 8807851 | doi = 10.1016/S1074-5521(96)90103-9 | doi-access = free }}</ref>

In mammalian cells, the much-studied β<sub>2</sub>-adrenoceptor has been demonstrated to activate the ERK2 pathway after arrestin-mediated uncoupling of G-protein-mediated signaling. Therefore, it seems likely that some mechanisms previously believed related purely to receptor desensitisation are actually examples of receptors switching their signaling pathway, rather than simply being switched off.

In kidney cells, the [[bradykinin receptor B2]] has been shown to interact directly with a protein tyrosine phosphatase. The presence of a tyrosine-phosphorylated [[immunoreceptor tyrosine-based inhibitory motif|ITIM]] (immunoreceptor tyrosine-based inhibitory motif) sequence in the B2 receptor is necessary to mediate this interaction and subsequently the antiproliferative effect of bradykinin.<ref>{{cite journal | vauthors = Duchene J, Schanstra JP, Pecher C, Pizard A, Susini C, Esteve JP, Bascands JL, Girolami JP | title = A novel protein-protein interaction between a G protein-coupled receptor and the phosphatase SHP-2 is involved in bradykinin-induced inhibition of cell proliferation | journal = The Journal of Biological Chemistry | volume = 277 | issue = 43 | pages = 40375–83 | date = October 2002 | pmid = 12177051 | doi = 10.1074/jbc.M202744200 | doi-access = free }}</ref>

====GPCR-independent signaling by heterotrimeric G-proteins====

Although it is a relatively immature area of research, it appears that heterotrimeric G-proteins may also take part in non-GPCR signaling. There is evidence for roles as signal transducers in nearly all other types of receptor-mediated signaling, including [[integrins]], [[receptor tyrosine kinases]] (RTKs), [[cytokine receptors]] ([[JAK-STAT signaling pathway|JAK/STATs]]), as well as modulation of various other "accessory" proteins such as [[guanine nucleotide exchange factor|GEFs]], [[guanosine nucleotide dissociation inhibitors|guanine-nucleotide dissociation inhibitors]] (GDIs) and [[protein phosphatases]]. There may even be specific proteins of these classes whose primary function is as part of GPCR-independent pathways, termed activators of G-protein signalling (AGS). Both the ubiquity of these interactions and the importance of Gα vs. Gβγ subunits to these processes are still unclear.

==Details of cAMP and PIP2 pathways==
[[File:Proteinkinase 1.svg|thumb|250px|Activation effects of cAMP on protein kinase A]]
[[File:The effect of Rs and Gs in cAMP signal pathway.jpg|thumb|250px|The effect of Rs and Gs in cAMP signal pathway]]
[[File:The effect of Ri and Gi in cAMP signal pathway.jpg|thumb|250px|The effect of Ri and Gi in cAMP signal pathway]]
There are two principal signal transduction pathways involving the [[G protein-coupled receptors|G protein-linked receptors]]: the [[cyclic adenosine monophosphate|cAMP]] signal pathway and the [[phosphatidylinositol]] signal pathway.<ref name="Gilman_1987"/>

===cAMP signal pathway===

{{Main|cAMP-dependent pathway}}
The cAMP signal transduction contains five main characters: stimulative [[hormone]] receptor (Rs) or inhibitory [[hormone receptor]] (Ri); stimulative regulative G-protein (Gs) or inhibitory regulative G-protein (Gi); [[adenylyl cyclase]]; [[protein kinase A|protein kinase&nbsp;A]] (PKA); and cAMP [[phosphodiesterase]].

Stimulative hormone receptor (Rs) is a receptor that can bind with stimulative signal molecules, while inhibitory hormone receptor (Ri) is a receptor that can bind with inhibitory signal molecules.

Stimulative regulative G-protein is a G-protein linked to stimulative hormone receptor (Rs), and its α subunit upon activation could stimulate the activity of an enzyme or other intracellular metabolism. On the contrary, inhibitory regulative G-protein is linked to an inhibitory hormone receptor, and its α subunit upon activation could inhibit the activity of an enzyme or other intracellular metabolism.

Adenylyl cyclase is a 12-transmembrane glycoprotein that catalyzes the conversion of ATP to cAMP with the help of cofactor Mg<sup>2+</sup> or Mn<sup>2+</sup>. The cAMP produced is a second messenger in cellular metabolism and is an allosteric activator of protein kinase A.

Protein kinase&nbsp;A is an important enzyme in cell metabolism due to its ability to regulate cell metabolism by phosphorylating specific committed enzymes in the metabolic pathway. It can also regulate specific gene expression, cellular secretion, and membrane permeability. The protein enzyme contains two catalytic subunits and two regulatory subunits. When there is no cAMP, the complex is inactive. When cAMP binds to the regulatory subunits, their conformation is altered, causing the dissociation of the regulatory subunits, which activates protein kinase A and allows further biological effects.

These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5'-AMP and inactivates protein kinase&nbsp;A.

===Phosphatidylinositol signal pathway===

{{Main|IP3/DAG pathway}}
In the [[phosphatidylinositol]] signal pathway, the extracellular signal molecule binds with the G-protein receptor (G<sub>q</sub>) on the cell surface and activates [[phospholipase C]], which is located on the [[cell membrane|plasma membrane]]. The [[lipase]] hydrolyzes [[phosphatidylinositol 4,5-bisphosphate]] (PIP2) into two second messengers: [[inositol trisphosphate|inositol 1,4,5-trisphosphate (IP3)]] and [[diacylglycerol]] (DAG). IP3 binds with the [[IP3 receptor]] in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca<sup>2+</sup> channels. DAG helps activate [[protein kinase C]] (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses.

The effects of Ca<sup>2+</sup> are also remarkable: it cooperates with DAG in activating PKC and can activate the [[Ca2+/calmodulin-dependent protein kinase|CaM kinase]] pathway, in which calcium-modulated protein [[calmodulin]] (CaM) binds Ca<sup>2+</sup>, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes. The kinase then phosphorylates target enzymes, regulating their activities. The two signal pathways are connected together by Ca<sup>2+</sup>-CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway.

==Receptor regulation==

GPCRs become desensitized when exposed to their ligand for a long period of time. There are two recognized forms of desensitization: 1) [[homologous desensitization]], in which the activated GPCR is downregulated; and 2) [[heterologous desensitization]], wherein the activated GPCR causes downregulation of a different GPCR. The key reaction of this downregulation is the [[phosphorylation]] of the intracellular (or [[cytoplasm]]ic) receptor domain by [[protein kinase]]s.

===Phosphorylation by cAMP-dependent protein kinases===

Cyclic AMP-dependent protein kinases ([[protein kinase A]]) are activated by the signal chain coming from the G protein (that was activated by the receptor) via [[adenylate cyclase]] and [[cyclic AMP]] (cAMP). In a ''feedback mechanism'', these activated kinases phosphorylate the receptor. The longer the receptor remains active the more kinases are activated and the more receptors are phosphorylated. In [[beta-2 adrenergic receptor|β<sub>2</sub>-adrenoceptor]]s, this phosphorylation results in the switching of the coupling from the G<sub>s</sub> class of G-protein to the [[Gi alpha subunit|G<sub>i</sub>]] class.<ref name="pmid11053129">{{cite journal | vauthors = Chen-Izu Y, Xiao RP, Izu LT, Cheng H, Kuschel M, Spurgeon H, Lakatta EG | title = G(i)-dependent localization of beta(2)-adrenergic receptor signaling to L-type Ca(2+) channels | journal = Biophysical Journal | volume = 79 | issue = 5 | pages = 2547–56 | date = November 2000 | pmid = 11053129 | pmc = 1301137 | doi = 10.1016/S0006-3495(00)76495-2 | bibcode = 2000BpJ....79.2547C }}</ref> cAMP-dependent PKA mediated phosphorylation can cause heterologous desensitisation in receptors other than those activated.<ref name="pmid14744258">{{cite journal | vauthors = Tan CM, Brady AE, Nickols HH, Wang Q, Limbird LE | title = Membrane trafficking of G protein-coupled receptors | journal = Annual Review of Pharmacology and Toxicology | volume = 44 | issue = 1 | pages = 559–609 | year = 2004 | pmid = 14744258 | doi = 10.1146/annurev.pharmtox.44.101802.121558 }}</ref>

===Phosphorylation by GRKs===

The [[G protein-coupled receptor kinases]] (GRKs) are protein kinases that phosphorylate only active GPCRs.<ref name="Trimarco2013">{{cite journal | vauthors = Santulli G, Trimarco B, Iaccarino G | title = G-protein-coupled receptor kinase 2 and hypertension: molecular insights and pathophysiological mechanisms | journal = High Blood Pressure & Cardiovascular Prevention | volume = 20 | issue = 1 | pages = 5–12 | date = March 2013 | pmid = 23532739 | doi = 10.1007/s40292-013-0001-8 | s2cid = 45674941 }}</ref> G-protein-coupled receptor kinases (GRKs) are key modulators of G-protein-coupled receptor (GPCR) signaling. They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphorylation rapidly initiates profound impairment of receptor signaling and desensitization. Activity of GRKs and subcellular targeting is tightly regulated by interaction with receptor domains, G protein subunits, lipids, anchoring proteins and calcium-sensitive proteins.<ref name="pmid14499340">{{cite journal | vauthors = Penela P, Ribas C, Mayor F | title = Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases | journal = Cellular Signalling | volume = 15 | issue = 11 | pages = 973–81 | date = November 2003 | pmid = 14499340 | doi = 10.1016/S0898-6568(03)00099-8 }}</ref>

Phosphorylation of the receptor can have two consequences:

# ''Translocation'': The receptor is, along with the part of the membrane it is embedded in, brought to the inside of the cell, where it is dephosphorylated within the acidic vesicular environment<ref name="pmid8995214">{{cite journal | vauthors = Krueger KM, Daaka Y, Pitcher JA, Lefkowitz RJ | title = The role of sequestration in G protein-coupled receptor resensitization. Regulation of beta2-adrenergic receptor dephosphorylation by vesicular acidification | journal = The Journal of Biological Chemistry | volume = 272 | issue = 1 | pages = 5–8 | date = January 1997 | pmid = 8995214 | doi = 10.1074/jbc.272.1.5 | doi-access = free }}</ref> and then brought back. This mechanism is used to regulate long-term exposure, for example, to a hormone, by allowing resensitisation to follow desensitisation. Alternatively, the receptor may undergo lysosomal degradation, or remain internalised, where it is thought to participate in the initiation of signalling events, the nature of which depending on the internalised vesicle's subcellular localisation.<ref name="pmid14744258"/>
# ''[[Arrestin]] linking'': The phosphorylated receptor can be linked to ''arrestin'' molecules that prevent it from binding (and activating) G proteins, in effect switching it off for a short period of time. This mechanism is used, for example, with [[rhodopsin]] in [[retina]] cells to compensate for exposure to bright light. In many cases, arrestin's binding to the receptor is a prerequisite for translocation. For example, beta-arrestin bound to β<sub>2</sub>-adrenoreceptors acts as an adaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus, the arrestin here acts as a scaffold assembling the components needed for clathrin-mediated endocytosis of β<sub>2</sub>-adrenoreceptors.<ref name="pmid10770944">{{cite journal | vauthors = Laporte SA, Oakley RH, Holt JA, Barak LS, Caron MG | title = The interaction of beta-arrestin with the AP-2 adaptor is required for the clustering of beta 2-adrenergic receptor into clathrin-coated pits | journal = The Journal of Biological Chemistry | volume = 275 | issue = 30 | pages = 23120–6 | date = July 2000 | pmid = 10770944 | doi = 10.1074/jbc.M002581200 | doi-access = free }}</ref><ref name="pmid10097102">{{cite journal | vauthors = Laporte SA, Oakley RH, Zhang J, Holt JA, Ferguson SS, Caron MG, Barak LS | title = The beta2-adrenergic receptor/betaarrestin complex recruits the clathrin adaptor AP-2 during endocytosis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 7 | pages = 3712–7 | date = March 1999 | pmid = 10097102 | pmc = 22359 | doi = 10.1073/pnas.96.7.3712 | bibcode = 1999PNAS...96.3712L | doi-access = free }}</ref>

===Mechanisms of GPCR signal termination===

As mentioned above, G-proteins may terminate their own activation due to their intrinsic [[GTPase|GTP→GDP hydrolysis]] capability. However, this reaction proceeds at a slow [[rate constant|rate]] (≈0.02 times/sec) and, thus, it would take around 50 seconds for any single G-protein to deactivate if other factors did not come into play. Indeed, there are around 30 [[protein isoform|isoforms]] of [[regulator of G protein signaling|RGS proteins]] that, when bound to Gα through their [[GTPase activating protein|GAP domain]], accelerate the hydrolysis rate to ≈30 times/sec. This 1500-fold increase in rate allows for the cell to respond to external signals with high speed, as well as spatial [[angular resolution|resolution]] due to limited amount of [[second messenger]] that can be generated and limited distance a G-protein can diffuse in 0.03 seconds. For the most part, the RGS proteins are [[promiscuous]] in their ability to deactivate G-proteins, while which RGS is involved in a given signaling pathway seems more determined by the tissue and GPCR involved than anything else. In addition, RGS proteins have the additional function of increasing the rate of GTP-GDP exchange at GPCRs, (i.e., as a sort of co-GEF) further contributing to the time resolution of GPCR signaling.

In addition, the GPCR may be [[homologous desensitization|desensitized]] itself. This can occur as:

# a direct result of [[receptor theory|ligand occupation]], wherein the change in [[protein conformation|conformation]] allows recruitment of [[G protein-coupled receptor kinase|GPCR-Regulating Kinases]] (GRKs), which go on to [[phosphorylation|phosphorylate]] various [[serine]]/[[threonine]] residues of IL-3 and the C-terminal tail. Upon GRK phosphorylation, the GPCR's affinity for [[arrestin|β-arrestin]] (β-arrestin-1/2 in most tissues) is increased, at which point β-arrestin may bind and act to both [[sterically]] hinder G-protein coupling as well as initiate the process of [[receptor-mediated endocytosis|receptor internalization]] through [[clathrin-mediated endocytosis]]. Because only the liganded receptor is desensitized by this mechanism, it is called [[homologous desensitization]]
# the affinity for β-arrestin may be increased in a ligand occupation and GRK-independent manner through phosphorylation of different ser/thr sites (but also of IL-3 and the C-terminal tail) by PKC and PKA. These phosphorylations are often sufficient to impair G-protein coupling on their own as well.<ref name="pmid18193069">{{cite journal | vauthors = Tobin AB | title = G-protein-coupled receptor phosphorylation: where, when and by whom | journal = British Journal of Pharmacology | volume = 153 | issue = Suppl 1| pages = S167–76 | date = March 2008 | pmid = 18193069 | pmc = 2268057 | doi = 10.1038/sj.bjp.0707662 }}</ref>
# PKC/PKA may, instead, phosphorylate GRKs, which can also lead to GPCR phosphorylation and β-arrestin binding in an occupation-independent manner. These latter two mechanisms allow for desensitization of one GPCR due to the activities of others, or [[heterologous desensitization]]. GRKs may also have GAP domains and so may contribute to inactivation through non-[[kinase]] mechanisms as well. A combination of these mechanisms may also occur.

Once β-arrestin is bound to a GPCR, it undergoes a conformational change allowing it to serve as a scaffolding protein for an adaptor complex termed [[AP2 adaptors|AP-2]], which in turn recruits another protein called [[clathrin]]. If enough receptors in the local area recruit clathrin in this manner, they aggregate and the [[plasma membrane|membrane]] buds inwardly as a result of interactions between the molecules of clathrin, in a process called [[opsonization]]. Once the pit has been pinched off the [[plasma membrane]] due to the actions of two other proteins called [[amphiphysin]] and [[dynamin]], it is now an [[endocytosis|endocytic]] [[vesicle (biology)|vesicle]]. At this point, the adapter molecules and clathrin have [[dissociated]], and the receptor is either [[protein targeting|trafficked]] back to the plasma membrane or targeted to [[lysosome]]s for [[proteolysis|degradation]].

At any point in this process, the β-arrestins may also recruit other proteins—such as the [[non-receptor tyrosine kinase]] (nRTK), [[Src (gene)|c-SRC]]—which may activate [[extracellular signal-regulated kinases|ERK1/2]], or other [[mitogen-activated protein kinase]] (MAPK) signaling through, for example, phosphorylation of the [[small GTPase]], [[Ras subfamily|Ras]], or recruit the proteins of the [[MAPK/ERK pathway|ERK cascade]] directly (i.e., [[Raf-1]], [[mitogen-activated protein kinase kinase|MEK]], ERK-1/2) at which point signaling is initiated due to their close proximity to one another. Another target of c-SRC are the dynamin molecules involved in endocytosis. Dynamins [[polymerization|polymerize]] around the neck of an incoming vesicle, and their phosphorylation by c-SRC provides the energy necessary for the conformational change allowing the final "pinching off" from the membrane.

===GPCR cellular regulation===
Receptor desensitization is mediated through a combination phosphorylation, β-arr binding, and endocytosis as described above. Downregulation occurs when endocytosed receptor is embedded in an endosome that is trafficked to merge with an organelle called a lysosome. Because lysosomal membranes are rich in proton pumps, their interiors have low pH (≈4.8 vs. the pH≈7.2 cytosol), which acts to denature the GPCRs. In addition, lysosomes contain many [[degradative enzyme]]s, including proteases, which can function only at such low pH, and so the peptide bonds joining the residues of the GPCR together may be cleaved. Whether or not a given receptor is trafficked to a lysosome, detained in endosomes, or trafficked back to the plasma membrane depends on a variety of factors, including receptor type and magnitude of the signal.
GPCR regulation is additionally mediated by gene transcription factors. These factors can increase or decrease gene transcription and thus increase or decrease the generation of new receptors (up- or down-regulation) that travel to the cell membrane.

==Receptor oligomerization==
{{Main|GPCR oligomer}}

G-protein-coupled receptor oligomerisation is a widespread phenomenon. One of the best-studied examples is the metabotropic [[GABAB receptor|GABA<sub>B</sub> receptor]]. This so-called constitutive receptor is formed by heterodimerization of [[GABBR1|GABA<sub>B</sub>R1]] and [[GABBR2|GABA<sub>B</sub>R2]] subunits. Expression of the GABA<sub>B</sub>R1 without the GABA<sub>B</sub>R2 in heterologous systems leads to retention of the subunit in the [[endoplasmic reticulum]]. Expression of the GABA<sub>B</sub>R2 subunit alone, meanwhile, leads to surface expression of the subunit, although with no functional activity (i.e., the receptor does not bind agonist and cannot initiate a response following exposure to agonist). Expression of the two subunits together leads to plasma membrane expression of functional receptor. It has been shown that GABA<sub>B</sub>R2 binding to GABA<sub>B</sub>R1 causes masking of a retention signal<ref name="pmid10939334">{{cite journal | vauthors = Margeta-Mitrovic M, Jan YN, Jan LY | title = A trafficking checkpoint controls GABA(B) receptor heterodimerization | journal = Neuron | volume = 27 | issue = 1 | pages = 97–106 | date = July 2000 | pmid = 10939334 | doi = 10.1016/S0896-6273(00)00012-X | s2cid = 15430860 | doi-access = free }}</ref> of functional receptors.<ref name="pmid9872316">{{cite journal | vauthors = White JH, Wise A, Main MJ, Green A, Fraser NJ, Disney GH, Barnes AA, Emson P, Foord SM, Marshall FH | title = Heterodimerization is required for the formation of a functional GABA(B) receptor | journal = Nature | volume = 396 | issue = 6712 | pages = 679–82 | date = December 1998 | pmid = 9872316 | doi = 10.1038/25354 | bibcode = 1998Natur.396..679W | s2cid = 4406311 }}</ref>

==Origin and diversification of the superfamily==
[[Signal transduction]] mediated by the superfamily of GPCRs dates back to the origin of [[Multicellular organism|multicellularity]]. Mammalian-like GPCRs are found in [[fungi]], and have been classified according to the [[GRAFS]] classification system based on GPCR fingerprints.<ref name=pmid22238661>{{cite journal | vauthors = Krishnan A, Almén MS, Fredriksson R, Schiöth HB | title = The origin of GPCRs: identification of mammalian like Rhodopsin, Adhesion, Glutamate and Frizzled GPCRs in fungi | journal = PLOS ONE | volume = 7 | issue = 1 | article-number = e29817 | year = 2012 | pmid = 22238661 | pmc = 3251606 | doi = 10.1371/journal.pone.0029817 | bibcode = 2012PLoSO...729817K | veditors = Xue C | doi-access = free }}</ref> Identification of the superfamily members across the [[eukaryotic]] domain, and comparison of the family-specific motifs, have shown that the superfamily of GPCRs have a common origin.<ref name=pmid21402729>{{cite journal | vauthors = Nordström KJ, Sällman Almén M, Edstam MM, Fredriksson R, Schiöth HB | title = Independent HHsearch, Needleman--Wunsch-based, and motif analyses reveal the overall hierarchy for most of the G protein-coupled receptor families | journal = Molecular Biology and Evolution | volume = 28 | issue = 9 | pages = 2471–80 | date = September 2011 | pmid = 21402729 | doi = 10.1093/molbev/msr061 | doi-access =  }}</ref> Characteristic motifs indicate that three of the five GRAFS families, ''[[Rhodopsin-like receptors|Rhodopsin]]'', [[adhesion G protein-coupled receptor|''Adhesion'']], and ''[[Frizzled]]'', evolved from the ''[[Dictyostelium]] discoideum'' cAMP receptors before the split of [[opisthokont]]s. Later, the ''[[Secretin receptor family|Secretin]]'' family evolved from the ''Adhesion'' GPCR receptor family before the split of [[nematode]]s.<ref name=pmid22238661/> Insect GPCRs appear to be in their own group and Taste2 is identified as descending from ''Rhodopsin''.<ref name=pmid21402729/> Note that the ''Secretin''/''Adhesion'' split is based on presumed function rather than signature, as the classical Class B (7tm_2, {{Pfam|PF00002}}) is used to identify both in the studies.

== See also ==
* [[G protein-coupled receptors database]]
* [[List of MeSH codes (D12.776)]]
* [[Metabotropic receptor]]
* [[Orphan receptor]]
* [[Pepducin]]s, a class of drug candidates targeted at GPCRs
* [[Receptor activated solely by a synthetic ligand]], a technique for control of cell signaling through synthetic GPCRs
* [[TOG superfamily]]

== References ==
{{Reflist}}

== Further reading ==
* {{cite journal | vauthors = Vassilatis DK, Hohmann JG, Zeng H, Li F, Ranchalis JE, Mortrud MT, Brown A, Rodriguez SS, Weller JR, Wright AC, Bergmann JE, Gaitanaris GA | title = The G protein-coupled receptor repertoires of human and mouse | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 100 | issue = 8 | pages = 4903–8 | date = April 2003 | pmid = 12679517 | pmc = 153653 | doi = 10.1073/pnas.0230374100 | bibcode = 2003PNAS..100.4903V | doi-access = free }}
* {{cite web |url= https://www.bio-balance.com/Ref.htm |title= GPCR Reference Library |quote= Reference for molecular and mathematical models for the initial receptor response |access-date= 11 August 2008}}
* {{cite web |url= https://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/popular-chemistryprize2012.pdf |archive-url=https://web.archive.org/web/20121018052846/http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/popular-chemistryprize2012.pdf |archive-date=2012-10-18 |url-status=live |title= The Nobel Prize in Chemistry 2012 |access-date= 10 October 2012}}

== External links ==
{{Commons category|G protein-coupled receptors}}
* {{MeSH name|G-protein-coupled+receptors}}
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* [https://www.creative-biogene.com/Product/GPCR-list-11.html GPCR Cell Line] {{Webarchive|url=https://web.archive.org/web/20150403202411/https://www.creative-biogene.com/Product/GPCR-list-11.html |date=3 April 2015 }}
* {{cite web |url= https://www.guidetopharmacology.org/GRAC/ReceptorFamiliesForward?type=GPCR |title= IUPHAR/BPS Guide to PHARMACOLOGY Database (GPCRs) |work= IUPHAR Database |publisher= University of Edinburgh / International Union of Basic and Clinical Pharmacology |access-date= 6 February 2019}}
* {{cite web |url= https://docs.gpcrdb.org/about.html |title= GPCRdb |quote= Data, diagrams and web tools for G protein-coupled receptors (GPCRs).}}; {{cite journal | vauthors = Munk C, Isberg V, Mordalski S, Harpsøe K, Rataj K, Hauser AS, Kolb P, Bojarski AJ, Vriend G, Gloriam DE | title = GPCRdb: the G protein-coupled receptor database - an introduction | journal = British Journal of Pharmacology | volume = 173 | issue = 14 | pages = 2195–207 | date = July 2016 | pmid = 27155948 | pmc = 4919580 | doi = 10.1111/bph.13509 }}
* {{cite web |url= https://www.gproteincoupledreceptors.net/ |title= G Protein-Coupled Receptors on the NET |quote= a classification of GPCRs |access-date= 10 November 2010 |archive-date= 23 July 2011 |archive-url= https://web.archive.org/web/20110723135805/http://www.gproteincoupledreceptors.net/ }}
* {{cite web |url =https://gpcr.scripps.edu |title =PSI GPCR Network Center |quote =a Protein Structure Initiative:Biology Network Center aimed at determining the 3D structures of representative GPCR family proteins |access-date =11 July 2013 |archive-url =https://web.archive.org/web/20130725122424/https://gpcr.scripps.edu/ |archive-date =25 July 2013 }}
* [https://zhanglab.ccmb.med.umich.edu/GPCR-HGmod GPCR-HGmod] {{Webarchive|url=https://web.archive.org/web/20160201154439/https://zhanglab.ccmb.med.umich.edu/GPCR-HGmod/ |date=1 February 2016 }}, a database of 3D structural models of all human G-protein coupled receptors, built by the GPCR-[[I-TASSER]] pipeline {{cite journal | vauthors = Zhang J, Yang J, Jang R, Zhang Y | title = GPCR-I-TASSER: A Hybrid Approach to G Protein-Coupled Receptor Structure Modeling and the Application to the Human Genome | journal = Structure | volume = 23 | issue = 8 | pages = 1538–1549 | date = August 2015 | pmid = 26190572 | pmc = 4526412 | doi = 10.1016/j.str.2015.06.007 }}

{{Cell surface receptors}}
{{G protein-coupled receptors}}

[[Category:G protein-coupled receptors| ]]
[[Category:Biochemistry]]
[[Category:Integral membrane proteins]]
[[Category:Molecular biology]]
[[Category:Protein families]]
[[Category:Signal transduction]]
[[Category:Protein superfamilies]]