Neuropeptide

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File:Neuropeptide Y.png
Neuropeptide Y

Neuropeptides are chemical messengers made up of small chains of amino acids that are synthesized and released by neurons. Neuropeptides typically bind to G protein-coupled receptors (GPCRs) to modulate neural activity and other tissues like the gut, muscles, and heart.

Neuropeptides are synthesized from large precursor proteins which are cleaved and post-translationally processed then packaged into large dense core vesicles. Neuropeptides are often co-released with other neuropeptides and neurotransmitters in a single neuron, yielding a multitude of effects. Once released, neuropeptides can diffuse widely to affect a broad range of targets.

Neuropeptides are extremely ancient and highly diverse chemical messengers. Placozoans such as Trichoplax, extremely basal animals which do not possess neurons, use peptides for cell-to-cell communication in a way similar to the neuropeptides of higher animals.

Examples

Peptide signals play a role in information processing that is different from that of conventional neurotransmitters, and many appear to be particularly associated with specific behaviours. For example, in mammals oxytocin<ref>Template:Cite journal</ref> and vasopressin<ref>Template:Cite journal</ref> have striking and specific effects on social behaviours, including maternal behaviour and pair bonding. In invertebrates, CCAP has several functions including regulating heart rate,<ref>Template:Cite journal</ref> allatostatin<ref>Template:Cite journal</ref> and proctolin<ref>Template:Cite journal</ref> regulate food intake and growth, and bursicon<ref name="Huanga">Template:Cite journal</ref> controls tanning of the cuticle.

Synthesis

Neuropeptides are synthesized from inactive precursor proteins called prepropeptides.<ref name=":3">Template:Cite book</ref> Prepropeptides contain sequences for a family of distinct peptides and often contain duplicated copies of the same peptides, depending on the organism.<ref name="Evolution of neuropeptide signallin">Template:Cite journal</ref> In addition to the precursor peptide sequences, prepropeptides also contain a signal peptide, spacer peptides, and cleavage sites.<ref name=":6">Template:Cite web</ref> The signal peptide sequence guides the protein to the secretory pathway, starting at the endoplasmic reticulum. The signal peptide sequence is removed in the endoplasmic reticulum, yielding a propeptide. The propeptide travels to the Golgi apparatus where it is proteolytically cleaved and processed into multiple peptides. Peptides are packaged into dense core vesicles, where further cleaving and processing, such as C-terminal amidation, can occur. Dense core vesicles are transported throughout the neuron and can release peptides at the synaptic cleft, cell body, and along the axon.<ref name=":3" /><ref name=":4">Template:Cite journal</ref><ref name=":5">Template:Cite journal</ref><ref name=":1">Template:Cite journal</ref>

A single animal may use hundreds of different neuropeptides. In C. elegans, for example, 120 genes specify more than 250 neuropeptides.<ref>Template:Cite journal</ref>

Mechanism

Neuropeptides are released by dense core vesicles after depolarization of the cell. Compared to classical neurotransmitter signaling, neuropeptide signaling is more sensitive. Neuropeptide receptor affinity is in the nanomolar to micromolar range while neurotransmitter affinity is in the micromolar to millimolar range. Additionally, dense core vesicles contain a small amount of neuropeptide (3 - 10mM) compared to synaptic vesicles containing neurotransmitters (e.g. 100mM for acetylcholine).<ref name=":8">Template:Cite book</ref> Evidence shows that neuropeptides are released after high-frequency firing or bursts, distinguishing dense core vesicle from synaptic vesicle release.<ref name=":4" /> Neuropeptides utilize volume transmission and are not reuptaken quickly, allowing diffusion across broad areas (nm to mm) to reach targets. Almost all neuropeptides bind to G protein-coupled receptors (GPCRs), inducing second messenger cascades to modulate neural activity on long time-scales.<ref name=":3" /><ref name=":4" /><ref name=":5" />

Expression of neuropeptides in the nervous system is diverse. Neuropeptides are often co-released with other neuropeptides and neurotransmitters, yielding a diversity of effects depending on the combination of release.<ref name=":5" /><ref name=":0" /> For example, vasoactive intestinal peptide is typically co-released with acetylcholine.<ref name=":9">Template:Cite journal</ref> Neuropeptide release can also be specific. In Drosophila larvae, for example, eclosion hormone is expressed in just two neurons.<ref name=":1" />

Co-release

Neuropeptides are often co-released with other neurotransmitters and neuropeptides to modulate synaptic activity. Synaptic vesicles and dense core vesicles can have differential activation properties for release, resulting in context-dependent co-release combinations.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> For example, insect motor neurons are glutamatergic and some contain dense core vesicles with proctolin. At low frequency activation, only glutamate is released, yielding fast and rapid excitation of the muscle. At high frequency activation however, dense core vesicles release proctolin, inducing prolonged contractions.<ref>Template:Cite journal</ref> Thus, neuropeptide release can be fine-tuned to modulate synaptic activity in certain contexts.

Some regions of the nervous system are specialized to release distinctive sets of peptides. For example, the hypothalamus and the pituitary gland release peptides (e.g. TRH, GnRH, CRH, SST) that act as hormones<ref>Template:Cite web</ref><ref>Template:Cite journal</ref> In one subpopulation of the arcuate nucleus of the hypothalamus, three anorectic peptides are co-expressed: α-melanocyte-stimulating hormone (α-MSH), galanin-like peptide, and cocaine-and-amphetamine-regulated transcript (CART), and in another subpopulation two orexigenic peptides are co-expressed, neuropeptide Y and agouti-related peptide (AGRP).<ref>Template:Cite journal</ref> These peptides are all released in different combinations to signal hunger and satiation cues.<ref>Template:Cite journal</ref>

The following is a list of neuroactive peptides co-released with other neurotransmitters. Transmitter names are shown in bold.

Norepinephrine (noradrenaline). In neurons of the A2 cell group in the nucleus of the solitary tract), norepinephrine co-exists with:

GABA

Acetylcholine

Dopamine

Epinephrine (adrenaline)

Serotonin (5-HT)

Some neurons make several different peptides. For instance, vasopressin co-exists with dynorphin and galanin in magnocellular neurons of the supraoptic nucleus and paraventricular nucleus, and with CRF (in parvocellular neurons of the paraventricular nucleus)

Oxytocin in the supraoptic nucleus co-exists with enkephalin, dynorphin, cocaine-and amphetamine regulated transcript (CART) and cholecystokinin.

Receptor targets

Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.<ref>Template:Cite journal</ref>  Most peptides activate a single GPCR, while some activate multiple GPCRs (e.g. AstA, AstC, DTK).<ref name=":0">Template:Cite journal</ref> Peptide-GPCR binding relationships are highly conserved across animals. Aside from conserved structural relationships, some peptide-GPCR functions are also conserved across the animal kingdom. For example, neuropeptide F/neuropeptide Y signaling is structurally and functionally conserved between insects and mammals.<ref name=":0" />

Although peptides mostly target metabotropic receptors, there is some evidence that neuropeptides bind to other receptor targets. Peptide-gated ion channels (FMRFamide-gated sodium channels) have been found in snails and Hydra.<ref>Template:Cite journal</ref> Other examples of non-GPCR targets include: insulin-like peptides and tyrosine-kinase receptors in Drosophila and atrial natriuretic peptide and eclosion hormone with membrane-bound guanylyl cyclase receptors in mammals and insects.<ref>Template:Cite journal</ref>

Actions

Due to their modulatory and diffusive nature, neuropeptides can act on multiple time and spatial scales. A nearly complete map of these interactions is known for at least one small animal, C. elegans.<ref>Template:Cite journal</ref>

For many other animals, at least some neuropeptide actions are known, as shown in the Examples section above.

Evolution of Neuropeptide Signaling

Peptides are ancient signaling systems that are found in almost all animals on Earth.<ref name=":2">Template:Cite journal</ref><ref>Template:Cite journal</ref> Genome sequencing reveals evidence of neuropeptide genes in Cnidaria, Ctenophora, and Placozoa, some of oldest living animals with nervous systems or neural-like tissues.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="Evolution of neuropeptide signallin"/> Recent studies also show genomic evidence of neuropeptide processing machinery in metazoans and choanoflagellates, suggesting that neuropeptide signaling may predate the development of nervous tissues.<ref>Template:Cite journal</ref> Additionally, Ctenophore and Placozoa neural signaling is entirely peptidergic and lacks the major amine neurotransmitters such as acetylcholine, dopamine, and serotonin.<ref>Template:Cite journal</ref><ref name=":2" /> This also suggests that neuropeptide signaling developed before amine neurotransmitters.

Applications

Neuropeptides and antagonists that bind to their receptors can be used as insecticides.<ref>Template:Cite journal</ref> These include both naturally occurring neuropeptides<ref>Template:Cite journal</ref> and synthetic compounds designed to block their receptors.<ref>Template:Cite journal</ref>

In humans, neuropeptides have been implicated in several human diseases.<ref>Template:Cite journal</ref> Antagonists to the related receptors may have clinical application.<ref>Template:Cite journal</ref>

Research history

In the early 1900s, chemical messengers were crudely extracted from whole animal brains and tissues and studied for their physiological effects. In 1931, von Euler and Gaddum, used a similar method to try and isolate acetylcholine but instead discovered a peptide substance that induced physiological changes including muscle contractions and depressed blood pressure. These effects were not abolished using atropine, ruling out the substance as acetylcholine.<ref name=":7">Template:Cite journal</ref><ref name=":9" />

In insects, proctolin was the first neuropeptide to be isolated and sequenced.<ref>Template:Cite book</ref><ref>Template:Cite journal</ref> In 1975, Alvin Starratt and Brian Brown extracted the peptide from hindgut muscles of the cockroach and found that its application enhanced muscle contractions. While Starratt and Brown initially thought of proctolin as an excitatory neurotransmitter, proctolin was later confirmed as a neuromodulatory peptide.<ref>Template:Cite book</ref>

David de Wied first used the term "neuropeptide" in the 1970s to delineate peptides derived from the nervous system.<ref name=":6" /><ref name=":8" />

References

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