View source for Cyclic guanosine monophosphate

{{chembox
| verifiedrevid = 476997295
| ImageFile = CGMP2.svg
| ImageSize = 220
| ImageAlt = Skeletal formula of cyclic guanosine monophosphate
| ImageFile1 = Cyclic-guanosine-monophosphate-anion-3D-spacefill.png
| ImageAlt1 = Space-filling model of the cyclic guanosine monophosphate anion
| IUPACName = Guanosine 3′,5′-(hydrogen phosphate)
| SystematicName = 2-Amino-9-[(4a''R'',6''R'',7''R'',7a''S'')-2,7-dihydroxy-2-oxotetrahydro-2''H'',4''H''-2λ<sup>5</sup>-furo[3,2-''d''][1,3,2]dioxaphosphol-6-yl]-3,9-dihydro-6''H''-purin-6-one
| OtherNames = cGMP; 3′,5′-cyclic GMP; 3′:5′-cyclic GMP; Guanosine cyclic monophosphate; Cyclic 3′,5′-GMP; Guanosine 3′,5′-cyclic phosphate
| Section1 = {{Chembox Identifiers
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 22734
| InChI = 1/C10H12N5O7P/c11-10-13-7-4(8(17)14-10)12-2-15(7)9-5(16)6-3(21-9)1-20-23(18,19)22-6/h2-3,5-6,9,16H,1H2,(H,18,19)(H3,11,13,14,17)/t3-,5-,6-,9-/m1/s1
| InChIKey = ZOOGRGPOEVQQDX-UUOKFMHZBB
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 395336
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C10H12N5O7P/c11-10-13-7-4(8(17)14-10)12-2-15(7)9-5(16)6-3(21-9)1-20-23(18,19)22-6/h2-3,5-6,9,16H,1H2,(H,18,19)(H3,11,13,14,17)/t3-,5-,6-,9-/m1/s1
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = ZOOGRGPOEVQQDX-UUOKFMHZSA-N
| CASNo_Ref = {{cascite|correct|CAS}}
| CASNo = 7665-99-8
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = H2D2X058MU
| PubChem = 24316
| IUPHAR_ligand = 2347
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 16356
| SMILES = O=C4/N=C(/N)Nc1c4ncn1[C@@H]2O[C@@H]3COP(=O)(O[C@H]3[C@H]2O)O
| MeSHName = Cyclic+GMP
  }}
| Section2 = {{Chembox Properties
| C=10|H=12|N=5|O=7|P=1
| Appearance = 
| Density = 
| MeltingPt = 
| BoilingPt = 
  }}
| Section3 = {{Chembox Hazards
| MainHazards = 
| FlashPt = 
| AutoignitionPt = 
  }}
}}
'''Cyclic guanosine monophosphate''' ('''cGMP''') is a [[cyclic nucleotide]] derived from [[guanosine triphosphate]] (GTP). cGMP acts as a [[second messenger]] much like [[cyclic AMP]].  Its most likely mechanism of action is activation of intracellular [[protein kinase]]s in response to the binding of [[Cell membrane|membrane]]-impermeable [[peptide hormone]]s to the external cell surface.<ref>{{cite journal | vauthors = Francis SH, Corbin JD | title = Cyclic nucleotide-dependent protein kinases: intracellular receptors for cAMP and cGMP action | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 36 | issue = 4 | pages = 275–328 | date = August 1999 | pmid = 10486703 | doi = 10.1080/10408369991239213 }}</ref> Through protein kinases activation, cGMP can relax smooth muscle.<ref>{{cite journal | vauthors = Carvajal JA, Germain AM, Huidobro-Toro JP, Weiner CP | title = Molecular mechanism of cGMP-mediated smooth muscle relaxation | journal = Journal of Cellular Physiology | volume = 184 | issue = 3 | pages = 409–420 | date = September 2000 | pmid = 10911373 | doi = 10.1002/1097-4652(200009)184:3<409::aid-jcp16>3.0.co;2-k | s2cid = 22530053 | doi-access = free }}</ref> cGMP concentration in urine can be measured for kidney function and diabetes detection.<ref>{{cite journal | vauthors = Chaykovska L, Heunisch F, von Einem G, Hocher CF, Tsuprykov O, Pavkovic M, Sandner P, Kretschmer A, Chu C, Elitok S, Stasch JP, Hocher B | display-authors = 6 | title = Urinary cGMP predicts major adverse renal events in patients with mild renal impairment and/or diabetes mellitus before exposure to contrast medium | journal = PLOS ONE | volume = 13 | issue = 4 | article-number = e0195828 | date = 2018-04-12 | pmid = 29649334 | pmc = 5896998 | doi = 10.1371/journal.pone.0195828 | bibcode = 2018PLoSO..1395828C | editor-first = Tatsuo | editor-last = Shimosawa | doi-access = free }}</ref>

== History ==
Cyclic guanosine monophosphate (cGMP) research began after cGMP and [[Cyclic adenosine monophosphate|cyclic adenosine monophosphate (cAMP)]] were identified as cellular components and potentially involved with cellular regulation.<ref name=":0">{{Citation |last1=Kots |first1=Alexander Y. |title=A Short History of cGMP, Guanylyl Cyclases, and cGMP-Dependent Protein Kinases |date=2009 |work=cGMP: Generators, Effectors and Therapeutic Implications |volume=191 |pages=1–14 |editor-last=Schmidt |editor-first=Harald H. H. W. |url=http://link.springer.com/10.1007/978-3-540-68964-5_1 |access-date=2024-11-27 |place=Berlin, Heidelberg |publisher=Springer Berlin Heidelberg |language=en |doi=10.1007/978-3-540-68964-5_1 |isbn=978-3-540-68960-7 |last2=Martin |first2=Emil |last3=Sharina |first3=Iraida G. |last4=Murad |first4=Ferid |pmid=19089322 |editor2-last=Hofmann |editor2-first=Franz |editor3-last=Stasch |editor3-first=Johannes-Peter|url-access=subscription |pmc=3932363 }}</ref> Upon the synthesis of cGMP in 1960,<ref name=":0" /> progress rapidly spread in the understanding of regulation and effects of cGMP. [[Earl Wilbur Sutherland Jr.|Earl W. Sutherland]] received the 1971 [[Nobel Prize in Physiology or Medicine|Nobel Prize in Medicine]] for his work with [[Cyclic adenosine monophosphate|cAMP]] and [[Second messenger system|secondary messengers]]. This award sparked extensive research into [[Cyclic adenosine monophosphate|cAMP]], while cGMP received less attention, with its biological functions largely unknown until the 1980s.<ref name=":13">{{Cite journal |last1=Feil |first1=Robert |last2=Kemp-Harper |first2=Barbara |date=Feb 2006 |title=cGMP signalling: from bench to bedside: Conference on cGMP Generators, Effectors and Therapeutic Implications |journal=EMBO Reports |language=en |volume=7 |issue=2 |pages=149–153 |doi=10.1038/sj.embor.7400627 |pmid=16439998 |pmc=1369255 |issn=1469-221X}}</ref> During this period, two pivotal discoveries highlighted cGMP's role in cellular signaling: [[Atrial natriuretic peptide|atrial natriuretic peptide (ANP)]] was found to stimulate cGMP synthesis through the particulate [[Guanylate cyclase|guanylyl cyclase]] (pGC) receptor, and [[nitric oxide]] (NO), identified as the endothelium-derived relaxing factor, was shown to activate [[soluble guanylyl cyclase]] (sGC), producing cGMP to mediate [[vasodilation]] in smooth muscle cells.<ref name=":13"/> Further components involved with the cGMP were also identified such as cGMP-hydrolyzing [[phosphodiesterase]]s (PDEs) and cGMP-binding proteins.<ref name=":13"/> The awarding of the 1998 [[Nobel Prize]] to [[Robert F. Furchgott]], [[Louis Ignarro|Louis J. Ignarro]], and [[Ferid Murad]] for their discoveries in the NO-cGMP pathway renewed interest in cGMP research with the 1st International Conference on cGMP being held in 2003.<ref name=":13"/>

== Synthesis ==

[[Guanylate cyclase]] (GC) [[catalyst|catalyzes]] cGMP synthesis.  This enzyme converts [[Guanosine triphosphate|GTP]] to cGMP.  Peptide hormones such as the [[atrial natriuretic factor]] activate membrane-bound GC, while soluble GC (sGC) is typically activated by [[nitric oxide]] to stimulate cGMP synthesis. sGC can be inhibited by ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one).<ref>{{cite journal | vauthors = Garthwaite J, Southam E, Boulton CL, Nielsen EB, Schmidt K, Mayer B | title = Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one | journal = Molecular Pharmacology | volume = 48 | issue = 2 | pages = 184–188 | date = August 1995 | pmid = 7544433 | url = https://molpharm.aspetjournals.org/content/48/2/184 }}</ref>[[File:Cyclic-guanosine-monophosphate-anion-ball-and-stick.png|thumb|Ball and Stick model of the cyclic guanosine monophosphate molecule, Color code: Carbon, C: black Hydrogen, H: white Oxygen, O: red Nitrogen, N: blue   Phosphorus, P: orange. |224x224px]]

==Functions==
cGMP acts as a regulator of ion channel conductance, glycogenolysis, cellular apoptosis, and platelet inhibition. cGMP relaxes smooth muscle tissue leading to vasodilation which increases blood flow. Additionally, cGMP is involved with neurogenesis and [[neuroplasticity]]. At presynaptic terminals in the [[striatum]], cGMP controls the efficacy of [[neurotransmitter]] release.<ref>{{cite journal | vauthors = Fieblinger T, Perez-Alvarez A, Lamothe-Molina PJ, Gee CE, Oertner TG | title = Presynaptic cGMP sets synaptic strength in the striatum and is important for motor learning | journal = EMBO Reports | volume = 23 | issue = 8 | article-number = e54361 | date = August 2022 | pmid = 35735260 | pmc = 9346481 | doi = 10.15252/embr.202154361 }}</ref>

cGMP is a secondary messenger in [[Visual phototransduction|phototransduction]] in the eye. In the photoreceptors of the mammalian eye, the presence of light activates [[phosphodiesterase]], which degrades cGMP. The [[sodium ion channel]]s in photoreceptors are cGMP-gated, so degradation of cGMP causes sodium channels to close, which leads to the hyperpolarization of the photoreceptor's plasma membrane and ultimately to visual information being sent to the brain.<ref>{{cite journal | vauthors = Brown RL, Strassmaier T, Brady JD, Karpen JW | title = The pharmacology of cyclic nucleotide-gated channels: emerging from the darkness | journal = Current Pharmaceutical Design | volume = 12 | issue = 28 | pages = 3597–3613 | year = 2006 | pmid = 17073662 | pmc = 2467446 | doi = 10.2174/138161206778522100 | id = NIHMSID: NIHMS47625 }}</ref>

cGMP is also seen to mediate the switching on of the attraction of [[apical dendrite]]s of [[pyramidal cells]] in [[Cerebral cortex|cortical layer V]] towards [[semaphorin-3a|semaphorin-3A]] (Sema3a).<ref>{{cite journal | vauthors = Polleux F, Morrow T, Ghosh A | title = Semaphorin 3A is a chemoattractant for cortical apical dendrites | journal = Nature | volume = 404 | issue = 6778 | pages = 567–573 | date = April 2000 | pmid = 10766232 | doi = 10.1038/35007001 | s2cid = 4365085 | bibcode = 2000Natur.404..567P }}</ref> Whereas the [[axons]] of pyramidal cells are repelled by Sema3a, the apical dendrites are attracted to it. The attraction is mediated by the increased levels of [[guanylate cyclase|soluble guanylate cyclase]] (sGC) that are present in the apical dendrites. sGC generates cGMP, leading to a sequence of chemical activations that result in the attraction towards Sema3a. The absence of sGC in the axon causes the repulsion from Sema3a. This strategy ensures the structural polarization of pyramidal neurons and takes place in embryonic development.

cGMP, like cAMP, gets synthesized when olfactory receptors receive odorous input.  cGMP is produced slowly and has a more sustained life than cAMP, which has implicated it in long-term cellular responses to odor stimulation, such as [[long-term potentiation]].  cGMP in the olfactory is synthesized by both membrane guanylyl cyclase (mGC) as well as soluble guanylyl cyclase (sGC).  Studies have found that cGMP synthesis in the olfactory is due to sGC activation by nitric oxide, a neurotransmitter. cGMP also requires increased intracellular levels of cAMP and the link between the two [[second messengers]] appears to be due to rising intracellular calcium levels.<ref>{{cite journal | vauthors = Pietrobon M, Zamparo I, Maritan M, Franchi SA, Pozzan T, Lodovichi C | title = Interplay among cGMP, cAMP, and Ca2+ in living olfactory sensory neurons in vitro and in vivo | journal = The Journal of Neuroscience | volume = 31 | issue = 23 | pages = 8395–8405 | date = June 2011 | pmid = 21653844 | pmc = 6623327 | doi = 10.1523/JNEUROSCI.6722-10.2011 | doi-access = free }}</ref>
[[File:Schematic of cGMP.jpg|thumb|375x375px|Schematic of cGMP and a broad overview of its effects]]

== Pathology ==

=== Role in Cardiovascular Events ===
The [[nitric oxide]] (NO)-cyclic guanosine monophosphate (cGMP)-phosphodiesterase (PDE) pathway has become a target in developing treatments for heart failure. A deficit in cGMP levels has been associated with adverse [[Cardiovascular disease|cardiovascular]] outcomes, promoting factors like [[Cardiac fibrosis|myocardial fibrosis]], [[vasoconstriction]], and [[inflammation]], all of which accelerate [[heart failure]] progression.<ref name=":32">{{Cite journal |last1=Emdin |first1=Michele |last2=Aimo |first2=Alberto |last3=Castiglione |first3=Vincenzo |last4=Vergaro |first4=Giuseppe |last5=Georgiopoulos |first5=Georgios |last6=Saccaro |first6=Luigi Francesco |last7=Lombardi |first7=Carlo Mario |last8=Passino |first8=Claudio |last9=Cerbai |first9=Elisabetta |last10=Metra |first10=Marco |last11=Senni |first11=Michele |date=2020-10-13 |title=Targeting Cyclic Guanosine Monophosphate to Treat Heart Failure: JACC Review Topic of the Week |url=https://linkinghub.elsevier.com/retrieve/pii/S0735109720363336 |journal=Journal of the American College of Cardiology |volume=76 |issue=15 |pages=1795–1807 |doi=10.1016/j.jacc.2020.08.031 |issn=0735-1097 |via=Elsevier Science Direct|url-access=subscription }}</ref> Some soluble [[guanylate cyclase]] (sGC) stimulators, have yielded promising outcomes in reducing cardiovascular events.<ref name=":32"/> Their effectiveness is thought to result from increased sensitivity of sGC to endogenous NO.

Elevated plasma cGMP levels, regulated predominantly by [[natriuretic peptide]]s (NP) rather than [[nitric oxide]] (NO), were found to correlate with a higher risk of heart failure, atherosclerotic cardiovascular disease, and [[Coronary artery disease|coronary heart disease]].<ref name=":4">{{Cite journal |last1=Zhao |first1=Di |last2=Guallar |first2=Eliseo |last3=Vaidya |first3=Dhananjay |last4=Ndumele |first4=Chiadi E. |last5=Ouyang |first5=Pamela |last6=Post |first6=Wendy S. |last7=Lima |first7=Joao A. |last8=Ying |first8=Wendy |last9=Kass |first9=David A. |last10=Hoogeveen |first10=Ron C. |last11=Shah |first11=Sanjiv J. |last12=Subramanya |first12=Vinita |last13=Michos |first13=Erin D. |date=2020-01-21 |title=Cyclic Guanosine Monophosphate and Risk of Incident Heart Failure and Other Cardiovascular Events: the ARIC Study |journal=Journal of the American Heart Association |language=en |volume=9 |issue=2 |article-number=e013966 |doi=10.1161/JAHA.119.013966 |pmid=31928156 |pmc=7033823 |issn=2047-9980}}</ref>

=== Role in Major Depression Disorder ===
The cGMP signaling pathway plays a role in the regulation of [[neuroplasticity]], an area of interest in understanding the pathophysiology of [[Major depressive disorder|major depressive disorder (MDD)]].<ref name=":2">{{Cite journal |last1=W. Reierson |first1=Gillian |last2=Guo |first2=Shuyu |last3=Mastronardi |first3=Claudio |last4=Licinio |first4=Julio |last5=Wong |first5=Ma-Li |date=2011-12-01 |title=cGMP Signaling, Phosphodiesterases and Major Depressive Disorder |url=http://www.eurekaselect.com/openurl/content.php?genre=article&issn=1570-159X&volume=9&issue=4&spage=715 |journal=Current Neuropharmacology |language=en |volume=9 |issue=4 |pages=715–727 |doi=10.2174/157015911798376271|pmid=22654729 |pmc=3263465 }}</ref> The cGMP signaling pathway in the brain operates as a [[second messenger system]], amplifying [[neurotransmitter]] signals, influencing [[gene expression]] and neuronal function. Within neurons, cGMP levels are modulated by guanylate cyclase [[enzyme]]s, which synthesize cGMP, and by PDEs, which degrade cGMP.<ref name=":2" />

Enhancing cGMP levels, either by stimulating guanylate cyclase or inhibiting PDEs, promotes [[neurogenesis]] and synaptic [[Neuroplasticity|plasticity]], particularly in brain regions implicated in [[Major depressive disorder|MDD]], such as the [[hippocampus]] and [[prefrontal cortex]].<ref name=":2" /> Animal studies also demonstrate that chronic [[antidepressant]] treatment can elevate cGMP levels in these areas.<ref name=":2" /> Genetic research has further highlighted specific polymorphisms in PDE genes associated with MDD susceptibility and treatment response.<ref name=":2" />

=== Role in Infectious Disease Pathogenesis ===
Certain pathogens, such as [[Escherichia coli|''Enterotoxigenic Escherichia coli'' (ETEC)]], elevate cGMP to evade host immune defenses and establish infection. ETEC's heat-stable toxin induces significant cGMP production within intestinal epithelial cells, and this cGMP is often secreted into the extracellular space, where it serves as a signaling molecule.<ref name=":5">{{Cite journal |last1=Motyka |first1=Natalya I. |last2=Stewart |first2=Sydney R. |last3=Hollifield |first3=Ian E. |last4=Kyllo |first4=Thomas R. |last5=Mansfield |first5=Joshua A. |last6=Norton |first6=Elizabeth B. |last7=Clements |first7=John D. |last8=Bitoun |first8=Jacob P. |date=2021-03-17 |editor-last=Torres |editor-first=Victor J. |title=Elevated Extracellular cGMP Produced after Exposure to Enterotoxigenic Escherichia coli Heat-Stable Toxin Induces Epithelial IL-33 Release and Alters Intestinal Immunity |url=https://journals.asm.org/doi/10.1128/IAI.00707-20 |journal=Infection and Immunity |language=en |volume=89 |issue=4 |doi=10.1128/IAI.00707-20 |pmid=33431701 |issn=0019-9567|pmc=8090939 }}</ref> Extracellular cGMP, in turn, triggers the release of IL-33 release which modulate inflammation and impact the immune system's ability to mount effective responses, dampening both innate and adaptive immunity.<ref name=":5" /><ref>{{Cite journal |last1=Wang |first1=Haixiu |last2=Zhong |first2=Zifu |last3=Luo |first3=Yu |last4=Cox |first4=Eric |last5=Devriendt |first5=Bert |date=2019-01-08 |title=Heat-Stable Enterotoxins of Enterotoxigenic Escherichia coli and Their Impact on Host Immunity |journal=Toxins |language=en |volume=11 |issue=1 |page=24 |doi=10.3390/toxins11010024 |doi-access=free |pmid=30626031 |issn=2072-6651|hdl=1854/LU-8588551 |hdl-access=free |pmc=6356903 }}</ref>

== Degradation ==

Numerous cyclic nucleotide [[phosphodiesterase]]s (PDE) can degrade cGMP by [[hydrolysis|hydrolyzing]] cGMP into 5'-GMP. PDE 5, -6 and -9 are cGMP-specific while PDE1, -2, -3, -10 and -11 can hydrolyse both cAMP and cGMP.

[[Phosphodiesterase inhibitor]]s prevent the degradation of cGMP, thereby enhancing and/or prolonging its effects. For example, [[Sildenafil]] (Viagra) and similar drugs enhance the vasodilatory effects of cGMP within the [[corpus cavernosum penis|corpus cavernosum]] by inhibiting PDE 5 (or PDE V). This is used as a treatment for [[erectile dysfunction]]. However, the drug can inhibit PDE6 in retina (albeit with less affinity than PDE5). This has been shown to result in loss of visual sensitivity but is unlikely to impair common visual tasks, except under conditions of reduced visibility when objects are already near visual threshold.<ref>{{cite journal | vauthors = Stockman A, Sharpe LT, Tufail A, Kell PD, Ripamonti C, Jeffery G | title = The effect of sildenafil citrate (Viagra) on visual sensitivity | journal = Journal of Vision | volume = 7 | issue = 8 | page = 4 | date = June 2007 | pmid = 17685811 | doi = 10.1167/7.8.4 | doi-access = free }}</ref> This effect is largely avoided by other PDE5 inhibitors, such as [[tadalafil]].<ref>{{cite journal | vauthors = Daugan A, Grondin P, Ruault C, Le Monnier de Gouville AC, Coste H, Linget JM, Kirilovsky J, Hyafil F, Labaudinière R | display-authors = 6 | title = The discovery of tadalafil: a novel and highly selective PDE5 inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione analogues | journal = Journal of Medicinal Chemistry | volume = 46 | issue = 21 | pages = 4533–4542 | date = October 2003 | pmid = 14521415 | doi = 10.1021/jm0300577 }}</ref>
[[File:CGMP-Rezeptoren.jpg|thumb|role of PKG in cellular system]]

== Protein kinase activation ==

The cGMP-dependent protein kinase (PKG) activation pathway begins with the production of cGMP by [[Guanylate cyclase|guanylyl cyclase]] enzymes, which can be activated by signaling molecules such as [[nitric oxide]] (NO) or [[natriuretic peptides]]. Elevated cGMP levels then lead to the activation of some protein-dependent kinases like PKG.<ref name=":13"/> For example, PKG ([[protein kinase G]]) is a [[protein dimer|dimer]] consisting of one [[catalysis|catalytic]] and one regulatory unit, with the regulatory units blocking the [[active site]]s of the catalytic units.

cGMP binds to sites on the regulatory units of PKG and activates the catalytic units, enabling them to phosphorylate their substrates. Unlike with the activation of some other protein kinases, notably PKA, the PKG is activated but the catalytic and regulatory units do not disassociate.

Once activated, PKG [[Phosphorylation|phosphorylates]] various target proteins, altering their function and contributing to cellular processes such as smooth muscle relaxation, ion channel regulation, and inhibition of platelet aggregation. This pathway is also significant in cardiovascular physiology, where it helps maintain vascular tone and [[blood pressure]].<ref name=":32"/>

== See also ==
* [[Cyclic adenosine monophosphate]] (cAMP)
* [[8-Bromoguanosine 3',5'-cyclic monophosphate]] (8-Br-cGMP)
* [[Guanosine triphosphate]] (GTP)
* [[Guanylate cyclase]]
* [[CGMP-dependent protein kinase|Protein Kinase G]]

== References ==
{{Reflist|2}}

{{Intracellular signaling peptides and proteins}}
{{Nucleobases, nucleosides, and nucleotides}}
{{Nitric oxide signaling}}

[[Category:Nucleotides]]
[[Category:Cyclic nucleotides]]
[[Category:Organophosphates]]
[[Category:Second messenger system]]