Neuropeptide

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.

Neuropeptide Y

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.

SynthesisEdit

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]

MechanismEdit

Neuropeptides are released by dense core vesicles after depolarization of the cell. Some 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][7] For example, vasoactive intestinal peptide is typically co-released with acetylcholine.[8] Neuropeptide release can also be specific. In Drosophila larvae, for example, eclosion hormone is expressed in just two neurons.[6]

DiscoveryEdit

The first neuropeptide, Substance P, was discovered by Ulf von Euler and John Gaddum in 1931.[4][9] 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.[9][10] Substance P was first purified and sequenced in 1971 by Michael Chang and Susan Leeman, revealing its 11 amino-acid peptide chain.[10] Similar methods were used to identify other neuropeptides in the early 1950s, such as vasopressin and oxytocin.[11][12]

In insects, proctolin was the first neuropeptide to be isolated and sequenced.[13][14] 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.[15]

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.[16]

Receptor targetsEdit

Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.[17]  Most peptides activate a single GPCR, while some activate multiple GPCRs (e.g. AstA, AstC, DTK).[7] 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.[7]

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.[18] 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.[19]

ExamplesEdit

Many populations of neurons have distinctive biochemical phenotypes. For example, in one subpopulation of about 3000 neurons in 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). These are not the only peptides in the arcuate nucleus; β-endorphin, dynorphin, enkephalin, galanin, ghrelin, growth-hormone releasing hormone, neurotensin, neuromedin U, and somatostatin are also expressed in subpopulations of arcuate neurons. These peptides are all released centrally and act on other neurons at specific receptors. The neuropeptide Y neurons also make the classical inhibitory neurotransmitter GABA.

Invertebrates also have many neuropeptides.[20] 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.

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. The following is a list of neuroactive peptides coexisting 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.

ReferencesEdit

  1. ^ a b c Mains RE, Eipper BA (1999). "The Neuropeptides". Basic Neurochemistry (6th ed.). Lippincott-Raven. ISBN 978-0-397-51820-3.
  2. ^ 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. ^ "nEUROSTRESSPEP: Insect Neuropeptides". www.neurostresspep.eu. Retrieved 25 August 2021.
  4. ^ a b c d Hökfelt T, Bartfai T, Bloom F (August 2003). "Neuropeptides: opportunities for drug discovery". The Lancet. Neurology. 2 (8): 463–72. 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 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.
  8. ^ 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): 417–23. doi:10.1007/BF00247899. PMID 2767193. S2CID 19504097.
  9. ^ a b 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.
  10. ^ a b Chang MM, Leeman SE, Niall HD (July 1971). "Amino-acid sequence of substance P". Nature. 232 (29): 86–7. doi:10.1038/newbio232086a0. PMID 5285346.
  11. ^ du Vigneaud V, Ressler C, Trippett S (December 1953). "The sequence of amino acids in oxytocin, with a proposal for the structure of oxytocin". The Journal of Biological Chemistry. 205 (2): 949–57. doi:10.1016/S0021-9258(18)49238-1. PMID 13129273.
  12. ^ Turner RA, Pierce JG, du VIGNEAUD V (July 1951). "The purification and the amino acid content of vasopressin preparations". The Journal of Biological Chemistry. 191 (1): 21–8. doi:10.1016/S0021-9258(18)50947-9. PMID 14850440.
  13. ^ 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.
  14. ^ Starratt AN, Brown BE (October 1975). "Structure of the pentapeptide proctolin, a proposed neurotransmitter in insects". Life Sciences. 17 (8): 1253–6. doi:10.1016/0024-3205(75)90134-4. PMID 576.
  15. ^ Tanaka Y (2016). "Proctolin". Handbook of Hormones. doi:10.1016/B978-0-12-801028-0.00067-2. ISBN 9780128010280.
  16. ^ Burbach JP (2011). "What are neuropeptides?". Methods in Molecular Biology. 789: 1–36. doi:10.1007/978-1-61779-310-3_1. ISBN 978-1-61779-309-7. PMID 21922398.
  17. ^ Brody T, Cravchik A (July 2000). "Drosophila melanogaster G protein-coupled receptors". The Journal of Cell Biology. 150 (2): F83-8. doi:10.1083/jcb.150.2.f83. PMC 2180217. PMID 10908591.
  18. ^ 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): 11958–65. doi:10.1074/jbc.M109.059998. PMC 2852933. PMID 20159980.
  19. ^ 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): 13371–6. Bibcode:2009PNAS..10613371C. doi:10.1073/pnas.0812593106. PMC 2726410. PMID 19666575.
  20. ^ Elphick MR, Mirabeau O, Larhammar D (February 2018). "Evolution of neuropeptide signalling systems". The Journal of Experimental Biology. 221 (Pt 3): 2528–2543. doi:10.1093/molbev/msy160. PMC 6188537.

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