Neuropeptide

Short description: Peptides released by neurons as intercellular messengers

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.

There are over 100 known neuropeptides, representing the largest and most diverse class of signaling molecules in the nervous system. Neuropeptides are synthesized from large precursor proteins which are cleaved and post-translationally processed then packaged into 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.

## Contents

* 1 Synthesis
* 2 Mechanism
* 3 Discovery
* 4 Receptor targets
* 5 Actions
* 5.1 Corelease
* 6 Evolution of Neuropeptide Signaling
* 7 Examples
* 8 References
* 9 External links

## Synthesis

Neuropeptides are synthesized from large, inactive precursor proteins called prepropeptides.[1] Prepropeptides contain sequences for a family of distinct peptides and often contain repeated copies of the same peptides, depending on the organism.[2] In addition to the precursor peptide sequences, prepropeptides also contain a signal peptide, spacer peptides, and cleavage sites.[3] 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.[1][4][5][6]

## 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).[7] Evidence shows that neuropeptides are released after high-frequency firing or bursts, distinguishing dense core vesicle from synaptic vesicle release.[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 GPCRs, inducing second messenger cascades to modulate neural activity on long time-scales.[1][4][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.[5][8] For example, vasoactive intestinal peptide is typically co-released with acetylcholine.[9] Neuropeptide release can also be specific. In Drosophila larvae, for example, eclosion hormone is expressed in just two neurons.[6]

## Discovery

The first neuropeptide, Substance P, was discovered by Ulf von Euler and John Gaddum in 1931.[4][10] In the early 1900s, chemical messengers were crudely extracted from whole animal brains and tissues and studied for their physiological effects. In an effort to isolate and study acetylcholine, von Euler and Gaddum made a crude powder extract from whole equine brain and intestine and found that it induced muscle contractions and depressed blood pressure. The effects were not abolished by atropine and thus could not solely be attributed to acetylcholine.[10][11] Substance P was first purified and sequenced in 1971 by Michael Chang and Susan Leeman, revealing its 11 amino-acid peptide chain.[11] Similar methods were used to identify other neuropeptides in the early 1950s, such as vasopressin and oxytocin.[12][13]

In insects, proctolin was the first neuropeptide to be isolated and sequenced.[14][15] In 1975, Alvin Starratt and Brian Brown extracted the pentapeptide 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.[16]

The term “neuropeptide” was first used in the 1970s by David de Wied, who studied the effects of the peptide hormones ACTH, MSH, and vasopressin on learning and memory.[17]

## Receptor targets

Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.[18] Most peptides activate a single GPCR, while some activate multiple GPCRs (e.g. AstA, AstC, DTK).[8] 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.[8]

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.[19] 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.[20]

## Actions

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

Due to their modulatory and diffusive nature, neuropeptides can act on multiple time and spatial scales. Below are some examples of neuropeptide actions:

### Corelease

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 corelease combinations.[21][22][23] 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.[24] 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[25][26] In one subpoplation 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).[27] These peptides are all released in different combinations to signal hunger and satiation cues.[28]

The following is a list of neuroactive peptides coreleased 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:

* Galanin
* Enkephalin
* Neuropeptide Y

GABA

* Somatostatin (in the hippocampus)
* Cholecystokinin
* Neuropeptide Y (in the arcuate nucleus)

Acetylcholine

* VIP
* Substance P

Dopamine

* Cholecystokinin
* Neurotensin
* Glucagon-like peptide-1 (in the nucleus accumbens)

Epinephrine (adrenaline)

* Neuropeptide Y
* Neurotensin

Serotonin (5-HT)

* Substance P
* TRH
* Enkephalin

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.

## Evolution of Neuropeptide Signaling

Peptides are ancient signaling systems that are found in almost all animals on Earth (sponges are the exception).[29][30] Genome sequencing reveals evidence of neuropeptide genes in Cnidaria, Ctenophora, and Placozoa, some of oldest living animals with nervous systems or neural-like tissues.[31][32][33][2] 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.[34] Additionally, Ctenophore and Placozoa neural signaling is entirely peptidergic and lacks the major amine neurotransmitters such as acetylcholine, dopamine, and serotonin.[35][29] This also suggests that neuropeptide signaling developed before amine neurotransmitters.

## 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, oxytocin and vasopressin have striking and specific effects on social behaviours, including maternal behaviour and pair bonding. CCAP has several functions including regulating heart rate, allatostatin and proctolin regulate food intake and growth, bursicon controls tanning of the cuticle and corazonin has a role in cuticle pigmentation and moulting.

## References

1. ↑ 1.0 1.1 1.2 "The Neuropeptides". Basic Neurochemistry (6th ed.). Lippincott-Raven. 1999. ISBN 978-0-397-51820-3. https://www.ncbi.nlm.nih.gov/books/NBK28247/.
2. ↑ 2.0 2.1 "Evolution of neuropeptide signalling systems". The Journal of Experimental Biology 221 (Pt 3): jeb151092. February 2018. doi:10.1242/jeb.151092. PMID 29440283.
3. ↑ "nEUROSTRESSPEP: Insect Neuropeptides". http://www.neurostresspep.eu/diner/insectneuropeptides.
4. ↑ 4.0 4.1 4.2 4.3 "Neuropeptides: opportunities for drug discovery". The Lancet. Neurology 2 (8): 463–472. August 2003. doi:10.1016/S1474-4422(03)00482-4. PMID 12878434.
5. ↑ 5.0 5.1 5.2 "Overview of Neuropeptides: Awakening the Senses?". Headache 57 (Suppl 2): 37–46. May 2017. doi:10.1111/head.13084. PMID 28485842.
6. ↑ 6.0 6.1 "Recent advances in neuropeptide signaling in Drosophila, from genes to physiology and behavior". Progress in Neurobiology 179: 101607. August 2019. doi:10.1016/j.pneurobio.2019.02.003. PMID 30905728.
7. ↑ "The Neuropeptides" (in en). Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Lippincott-Raven. 1999. https://www.ncbi.nlm.nih.gov/books/NBK28247/.
8. ↑ 8.0 8.1 8.2 "Drosophila neuropeptides in regulation of physiology and behavior". Progress in Neurobiology 92 (1): 42–104. September 2010. doi:10.1016/j.pneurobio.2010.04.010. PMID 20447440.
9. ↑ "The cholinergic innervation of the rat cerebral cortex shows two distinct phases in development". Experimental Brain Research 76 (2): 417–423. July 1989. doi:10.1007/BF00247899. PMID 2767193.
10. ↑ 10.0 10.1 "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology 72 (1): 74–87. June 1931. doi:10.1113/jphysiol.1931.sp002763. PMID 16994201.
11. ↑ 11.0 11.1 "Amino-acid sequence of substance P". Nature 232 (29): 86–87. July 1971. doi:10.1038/newbio232086a0. PMID 5285346.
12. ↑ "The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin". The Journal of Biological Chemistry 205 (2): 949–957. December 1953. doi:10.1016/S0021-9258(18)49238-1. PMID 13129273.
13. ↑ "The purification and the amino acid content of vasopressin preparations". The Journal of Biological Chemistry 191 (1): 21–28. July 1951. doi:10.1016/S0021-9258(18)50947-9. PMID 14850440.
14. ↑ "Proctolin in Insects". Handbook of Biologically Active Peptides. 2006. pp. 177–181. doi:10.1016/B978-012369442-3/50030-1. ISBN 9780123694423.
15. ↑ "Structure of the pentapeptide proctolin, a proposed neurotransmitter in insects". Life Sciences 17 (8): 1253–1256. October 1975. doi:10.1016/0024-3205(75)90134-4. PMID 576.
16. ↑ "Proctolin". Handbook of Hormones. 2016. doi:10.1016/B978-0-12-801028-0.00067-2. ISBN 9780128010280.
17. ↑ "What Are Neuropeptides?". Neuropeptides. Methods in Molecular Biology. 789. 2011. pp. 1–36. doi:10.1007/978-1-61779-310-3_1. ISBN 978-1-61779-309-7.
18. ↑ "Drosophila melanogaster G protein-coupled receptors". The Journal of Cell Biology 150 (2): F83–F88. July 2000. doi:10.1083/jcb.150.2.f83. PMID 10908591.
19. ↑ "Three homologous subunits form a high affinity peptide-gated ion channel in Hydra". The Journal of Biological Chemistry 285 (16): 11958–11965. April 2010. doi:10.1074/jbc.M109.059998. PMID 20159980.
20. ↑ "Receptor guanylyl cyclases in Inka cells targeted by eclosion hormone". Proceedings of the National Academy of Sciences of the United States of America 106 (32): 13371–13376. August 2009. doi:10.1073/pnas.0812593106. PMID 19666575. Bibcode: 2009PNAS..10613371C.
21. ↑ "Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila". Frontiers in Cellular Neuroscience 12: 83. 2018-03-23. doi:10.3389/fncel.2018.00083. PMID 29651236.
22. ↑ "Neuropeptide transmission in brain circuits". Neuron 76 (1): 98–115. October 2012. doi:10.1016/j.neuron.2012.09.014. PMID 23040809.
23. ↑ "The roles of co-transmission in neural network modulation" (in English). Trends in Neurosciences 24 (3): 146–154. March 2001. doi:10.1016/S0166-2236(00)01723-9. PMID 11182454.
24. ↑ "Peptide cotransmitter at a neuromuscular junction". Science 221 (4607): 286–289. July 1983. doi:10.1126/science.6134339. PMID 6134339. Bibcode: 1983Sci...221..286A.
25. ↑ "The Nobel Prize in Physiology or Medicine 1977" (in en-US). https://www.nobelprize.org/prizes/medicine/1977/press-release/.
26. ↑ "Hypothalamic regulatory peptides and their receptors: cytochemical studies of their role in regulation at the adenohypophyseal level". Journal of Electron Microscopy Technique 19 (1): 21–41. September 1991. doi:10.1002/jemt.1060190104. PMID 1660066.
27. ↑ "CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis". Molecular Metabolism 7: 102–118. January 2018. doi:10.1016/j.molmet.2017.10.015. PMID 29146410.
28. ↑ "Anorectic brainstem peptides: more pieces to the puzzle". Trends in Endocrinology and Metabolism 14 (2): 60–65. March 2003. doi:10.1016/S1043-2760(02)00033-4. PMID 12591175.
29. ↑ 29.0 29.1 "Neuropeptides as Regulators of Behavior in Insects". Annual Review of Entomology 62: 35–52. January 2017. doi:10.1146/annurev-ento-031616-035500. PMID 27813667. https://lirias.kuleuven.be/handle/123456789/632231.
30. ↑ "The chemical brain hypothesis for the origin of nervous systems". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences 376 (1821): 20190761. March 2021. doi:10.1098/rstb.2019.0761. PMID 33550946.
31. ↑ "Neuropeptide repertoire and 3D anatomy of the ctenophore nervous system". Current Biology 31 (23): 5274–5285.e6. December 2021. doi:10.1016/j.cub.2021.09.005. PMID 34587474.
32. ↑ "Insight into the molecular and functional diversity of cnidarian neuropeptides". International Journal of Molecular Sciences 16 (2): 2610–2625. January 2015. doi:10.3390/ijms16022610. PMID 25625515.
33. ↑ "Molecular evolution of peptidergic signaling systems in bilaterians". Proceedings of the National Academy of Sciences of the United States of America 110 (22): E2028–E2037. May 2013. doi:10.1073/pnas.1219956110. PMID 23671109. Bibcode: 2013PNAS..110E2028M.
34. ↑ "Premetazoan Origin of Neuropeptide Signaling". Molecular Biology and Evolution 39 (4): msac051. April 2022. doi:10.1093/molbev/msac051. PMID 35277960.
35. ↑ "High Cell Diversity and Complex Peptidergic Signaling Underlie Placozoan Behavior". Current Biology 28 (21): 3495–3501.e2. November 2018. doi:10.1016/j.cub.2018.08.067. PMID 30344118.

## External links

| Wikimedia Commons has media related to Neuropeptide.

|

* Neuropeptides Journal
* Neuropeptides reference website (a comprehensive neuropeptide database)
* Neuropeptides eBook series
* Neuropeptide chapter in the C. elegans Wormbook excellent, and very accessible, discussion of neuropeptide biology in C. elegans

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Cell signaling / Signal transduction

Signaling pathways|

* GPCR
*   * Wnt
* RTK
* TGF beta
* MAPK/ERK
* Notch
* JAK-STAT
* Akt/PKB
* Fas apoptosis
* Hippo
* PI3K/AKT/mTOR pathway
* Integrin receptors

Agents|

| Receptor ligands|

* Hormones
* Neurotransmitters/Neuropeptides/Neurohormones
* Cytokines
* Growth factors
* Signaling molecules

|

Receptors|

* Cell surface
* Intracellular
* Co-receptor

Second messenger|

* cAMP-dependent pathway
* Ca2+ signaling
* Lipid signaling

Assistants:|

* Signal transducing adaptor protein
* Scaffold protein

Transcription factors|

* General
* Transcription preinitiation complex
* TFIID
* TFIIH

By distance|

* Juxtacrine
* Autocrine / Paracrine
* Endocrine

Other concepts|

* Intracrine action
* Neurocrine signaling
* Synaptic transmission
* Chemical synapse
* Neuroendocrine signaling
* Exocrine signalling
* Pheromones
* Mechanotransduction
* Phototransduction
* Ion channel gating
* Gap junction

* v
* t
* e

Peptides: neuropeptides

Hormones|

see hormones

Opioid peptides|

| Dynorphins|

* Dynorphin A
* Dynorphin A1–8
* Dynorphin B
* Big dynorphin
* Leumorphin
* α-Neoendorphin
* β-Neoendorphin

|

Endomorphins|

* Endomorphin-1
* Endomorphin-2

Endorphins|

* α-Endorphin
* β-Endorphin
* γ-Endorphin

Enkephalins|

* Met-enkephalin
* Leu-enkephalin

Others|

* Adrenorphin
* Amidorphin
* Hemorphin
* Hemorphin-4
* Nociceptin
* Opiorphin
* Spinorphin
* Valorphin

Other
neuropeptides|

| Kinins|

Bradykinins
Tachykinins: mammal

* Substance P
* Neurokinin A
* Neurokinin B

amphibian

* Kassinin
* Physalaemin

|

Neuromedins|

* B
* N
* S
* U

Orexins|

* A
* B

Other|

* Angiotensin
* Bombesin
* Calcitonin gene-related peptide
* Carnosine
* Cocaine- and amphetamine-regulated transcript
* Delta sleep-inducing peptide
* FMRFamide
* Galanin
* Galanin-like peptide
* Gastrin-releasing peptide
* Ghrelin
* Neuropeptide AF
* Neuropeptide FF
* Neuropeptide SF
* Neuropeptide VF
* Neuropeptide S
* Neuropeptide Y
* Neurophysins
* Neurotensin
* Pancreatic polypeptide
* Pituitary adenylate cyclase-activating peptide
* RVD-Hpα
* VGF

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