From Wikipedia, the free encyclopedia
(Redirected from Neuropeptides)

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 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 synthesized from inactive precursor proteins called prepropeptides.[1] Prepropeptides contain sequences for a family of distinct peptides and often contain duplicated 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]


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]


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. [10][9]

In insects, proctolin was the first neuropeptide to be isolated and sequenced.[11][12] 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.[13]

David de Wied first used the term "neuropeptide" in the 1970s to delineate peptides derived from the nervous system.[3][7]

Receptor targets[edit]

Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.[14]  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.[15] 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.[16]


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.

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


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.[17][18][19] 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.[20] 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[21][22] 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).[23] These peptides are all released in different combinations to signal hunger and satiation cues.[24]

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:




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.

Evolution of Neuropeptide Signaling[edit]

Peptides are ancient signaling systems that are found in almost all animals on Earth.[25][26] Genome sequencing reveals evidence of neuropeptide genes in Cnidaria, Ctenophora, and Placozoa, some of oldest living animals with nervous systems or neural-like tissues.[27][28][29][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.[30] Additionally, Ctenophore and Placozoa neural signaling is entirely peptidergic and lacks the major amine neurotransmitters such as acetylcholine, dopamine, and serotonin.[31][25] This also suggests that neuropeptide signaling developed before amine neurotransmitters.


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.


  1. ^ a b c Mains RE, Eipper BA (1999). "The Neuropeptides". Basic Neurochemistry (6th ed.). Lippincott-Raven. ISBN 978-0-397-51820-3.
  2. ^ a b Elphick MR, Mirabeau O, Larhammar D (February 2018). "Evolution of neuropeptide signalling systems". The Journal of Experimental Biology. 221 (Pt 3): jeb151092. doi:10.1242/jeb.151092. PMC 5818035. PMID 29440283.
  3. ^ a b "nEUROSTRESSPEP: Insect Neuropeptides". Retrieved 25 August 2021.
  4. ^ a b c Hökfelt T, Bartfai T, Bloom F (August 2003). "Neuropeptides: opportunities for drug discovery". The Lancet. Neurology. 2 (8): 463–472. doi:10.1016/S1474-4422(03)00482-4. PMID 12878434. S2CID 23326450.
  5. ^ a b c Russo AF (May 2017). "Overview of Neuropeptides: Awakening the Senses?". Headache. 57 (Suppl 2): 37–46. doi:10.1111/head.13084. PMC 5424629. PMID 28485842.
  6. ^ a b Nässel DR, Zandawala M (August 2019). "Recent advances in neuropeptide signaling in Drosophila, from genes to physiology and behavior". Progress in Neurobiology. 179: 101607. doi:10.1016/j.pneurobio.2019.02.003. PMID 30905728. S2CID 84846652.
  7. ^ a b Mains RE, Eipper BA (1999). "The Neuropeptides". Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition. Lippincott-Raven.
  8. ^ a b c Nässel DR, Winther AM (September 2010). "Drosophila neuropeptides in regulation of physiology and behavior". Progress in Neurobiology. 92 (1): 42–104. doi:10.1016/j.pneurobio.2010.04.010. PMID 20447440. S2CID 24350305.
  9. ^ a b Dori I, Parnavelas JG (July 1989). "The cholinergic innervation of the rat cerebral cortex shows two distinct phases in development". Experimental Brain Research. 76 (2): 417–423. doi:10.1007/BF00247899. PMID 2767193. S2CID 19504097.
  10. ^ V Euler US, Gaddum JH (June 1931). "An unidentified depressor substance in certain tissue extracts". The Journal of Physiology. 72 (1): 74–87. doi:10.1113/jphysiol.1931.sp002763. PMC 1403098. PMID 16994201.
  11. ^ Lange AB, Orchard I (2006). "Proctolin in Insects". Handbook of Biologically Active Peptides. pp. 177–181. doi:10.1016/B978-012369442-3/50030-1. ISBN 9780123694423.
  12. ^ Starratt AN, Brown BE (October 1975). "Structure of the pentapeptide proctolin, a proposed neurotransmitter in insects". Life Sciences. 17 (8): 1253–1256. doi:10.1016/0024-3205(75)90134-4. PMID 576.
  13. ^ Tanaka Y (2016). "Proctolin". Handbook of Hormones. doi:10.1016/B978-0-12-801028-0.00067-2. ISBN 9780128010280.
  14. ^ Brody T, Cravchik A (July 2000). "Drosophila melanogaster G protein-coupled receptors". The Journal of Cell Biology. 150 (2): F83–F88. doi:10.1083/jcb.150.2.f83. PMC 2180217. PMID 10908591.
  15. ^ Dürrnagel S, Kuhn A, Tsiairis CD, Williamson M, Kalbacher H, Grimmelikhuijzen CJ, et al. (April 2010). "Three homologous subunits form a high affinity peptide-gated ion channel in Hydra". The Journal of Biological Chemistry. 285 (16): 11958–11965. doi:10.1074/jbc.M109.059998. PMC 2852933. PMID 20159980.
  16. ^ Chang JC, Yang RB, Adams ME, Lu KH (August 2009). "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. Bibcode:2009PNAS..10613371C. doi:10.1073/pnas.0812593106. PMC 2726410. PMID 19666575.
  17. ^ Nässel DR (23 March 2018). "Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in Drosophila". Frontiers in Cellular Neuroscience. 12: 83. doi:10.3389/fncel.2018.00083. PMC 5885757. PMID 29651236.
  18. ^ van den Pol AN (October 2012). "Neuropeptide transmission in brain circuits". Neuron. 76 (1): 98–115. doi:10.1016/j.neuron.2012.09.014. PMC 3918222. PMID 23040809.
  19. ^ Nusbaum MP, Blitz DM, Swensen AM, Wood D, Marder E (March 2001). "The roles of co-transmission in neural network modulation". Trends in Neurosciences. 24 (3): 146–154. doi:10.1016/S0166-2236(00)01723-9. PMID 11182454. S2CID 8994646.
  20. ^ Adams ME, O'Shea M (July 1983). "Peptide cotransmitter at a neuromuscular junction". Science. 221 (4607): 286–289. Bibcode:1983Sci...221..286A. doi:10.1126/science.6134339. PMID 6134339.
  21. ^ "The Nobel Prize in Physiology or Medicine 1977". Retrieved 15 December 2021.
  22. ^ Childs GV, Westlund KN, Tibolt RE, Lloyd JM (September 1991). "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. doi:10.1002/jemt.1060190104. PMID 1660066.
  23. ^ Lau J, Farzi A, Qi Y, Heilbronn R, Mietzsch M, Shi YC, Herzog H (January 2018). "CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis". Molecular Metabolism. 7: 102–118. doi:10.1016/j.molmet.2017.10.015. PMC 5784325. PMID 29146410.
  24. ^ Luckman SM, Lawrence CB (March 2003). "Anorectic brainstem peptides: more pieces to the puzzle". Trends in Endocrinology and Metabolism. 14 (2): 60–65. doi:10.1016/S1043-2760(02)00033-4. PMID 12591175. S2CID 25055675.
  25. ^ a b Schoofs L, De Loof A, Van Hiel MB (January 2017). "Neuropeptides as Regulators of Behavior in Insects". Annual Review of Entomology. 62: 35–52. doi:10.1146/annurev-ento-031616-035500. PMID 27813667.
  26. ^ Jékely G (March 2021). "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. doi:10.1098/rstb.2019.0761. PMC 7935135. PMID 33550946.
  27. ^ Sachkova MY, Nordmann EL, Soto-Àngel JJ, Meeda Y, Górski B, Naumann B, et al. (December 2021). "Neuropeptide repertoire and 3D anatomy of the ctenophore nervous system". Current Biology. 31 (23): 5274–5285.e6. doi:10.1016/j.cub.2021.09.005. PMID 34587474. S2CID 238210404.
  28. ^ Takahashi T, Takeda N (January 2015). "Insight into the molecular and functional diversity of cnidarian neuropeptides". International Journal of Molecular Sciences. 16 (2): 2610–2625. doi:10.3390/ijms16022610. PMC 4346854. PMID 25625515.
  29. ^ Mirabeau O, Joly JS (May 2013). "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. Bibcode:2013PNAS..110E2028M. doi:10.1073/pnas.1219956110. PMC 3670399. PMID 23671109.
  30. ^ Yañez-Guerra LA, Thiel D, Jékely G (April 2022). "Premetazoan Origin of Neuropeptide Signaling". Molecular Biology and Evolution. 39 (4): msac051. doi:10.1093/molbev/msac051. PMC 9004410. PMID 35277960.
  31. ^ Varoqueaux F, Williams EA, Grandemange S, Truscello L, Kamm K, Schierwater B, et al. (November 2018). "High Cell Diversity and Complex Peptidergic Signaling Underlie Placozoan Behavior". Current Biology. 28 (21): 3495–3501.e2. doi:10.1016/j.cub.2018.08.067. PMID 30344118. S2CID 53044824.

External links[edit]