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{{Short description|Peptides released by neurons as intercellular messengers}}
{{Use dmy dates|date=March 2014}}
{{Use dmy dates|date=March 2014}}
[[Image:Neuropeptide Y.png|thumb|right|Neuropeptide Y]]
[[Image:Neuropeptide Y.png|thumb|right|Neuropeptide Y]]


'''Neuropeptides''' are chemical messengers made up of small chains of [[amino acid]]s that are synthesized and released by [[neuron]]s. Neuropeptides typically bind to [[G protein-coupled receptor]]s (GPCRs) to modulate neural activity and other tissues like the gut, muscles, and heart.
'''Neuropeptides''' are small [[protein]]s produced by [[neurons]] that act on [[G protein-coupled receptors]] and are responsible for slow-onset, long-lasting modulation of synaptic transmission. Neuropeptides often coexist with each other or with other [[neurotransmitters]] in a single neuron. According to their chemical nature, coexisting messengers are localized to different cell compartments: neuropeptides are packaged in large dense core vesicles,<ref name="UniProt">{{cite web |title=Neuronal dense core vesicle |url=https://www.uniprot.org/locations/SL-0526 |website=www.uniprot.org |access-date=20 December 2020}}</ref> whereas low-molecular weight neurotransmitters are stored in small [[synaptic vesicle]]s.


Neuropeptides are synthesized from large precursor proteins which are cleaved and post-translationally processed then packaged into dense core [[Vesicle (biology and chemistry)|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 conjugated to proteins or other carriers, such as [[liposomes]], may be used for targeting radioisotopes or drugs to cells, specialized endothelia, and normal or neoplastic tissues expressing the corresponding binding sites for diagnostic or therapeutic purposes.


Neuropeptides are extremely ancient and highly diverse chemical messengers. [[Placozoa|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.
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== Mechanism and synthesis ==
Neuropeptides are synthesized from large, inactive [[Protein precursor|precursor proteins]] called prepropeptides, which are cleaved into several active [[peptides]]. Prepropeptides often produce multiple copies of the same peptide or many different peptides.<ref>{{Cite journal|last1=Elphick|first1=Maurice R.|last2=Mirabeau|first2=Olivier|last3=Larhammar|first3=Dan|date=2018-02-01|title=Evolution of neuropeptide signalling systems|journal=Journal of Experimental Biology|language=en|volume=221|issue=3|pages=jeb151092|doi=10.1242/jeb.151092|issn=0022-0949|pmid=29440283|pmc=5818035}}</ref> The number of repeats of a peptide sequence often changed throughout evolution and served as a hotbed for genetic variation.


== Examples ==
Peptides are synthesized at the soma, entered into the secretory pathway to pass through the rER-[[Golgi complex]], further processed, then packaged into large '''dense core vesicles''' for transport down the [[axon]] or [[dendrite]]s.<ref name=":2">{{Cite journal|last1=Mains|first1=Richard E.|last2=Eipper|first2=Betty A.|date=1999|title=The Neuropeptides|url=https://www.ncbi.nlm.nih.gov/books/NBK28247/|journal=Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th Edition}}</ref><ref name=":1">{{Cite journal|last1=Nässel|first1=Dick R.|last2=Zandawala|first2=Meet|date=August 2019|title=Recent advances in neuropeptide signaling in Drosophila, from genes to physiology and behavior|journal=Progress in Neurobiology|volume=179|pages=101607|doi=10.1016/j.pneurobio.2019.02.003|issn=1873-5118|pmid=30905728}}</ref> The large '''dense core vesicles''' are often found in all parts of a neuron, including the [[soma (biology)|soma]], [[dendrites]], axonal swellings (varicosities) and nerve endings, whereas the small synaptic vesicles are mainly found in clusters at presynaptic locations.<ref name="pmid23040809">{{cite journal|vauthors=van den Pol AN|date=October 2012|title=Neuropeptide transmission in brain circuits|journal=Neuron|volume=76|issue=1|pages=98–115|doi=10.1016/j.neuron.2012.09.014|pmc=3918222|pmid=23040809}}</ref><ref name="pmid18845614">{{cite journal|vauthors=Leng G, Ludwig M|date=December 2008|title=Neurotransmitters and peptides: whispered secrets and public announcements|journal=The Journal of Physiology|volume=586|issue=23|pages=5625–32|doi=10.1113/jphysiol.2008.159103|pmc=2655398|pmid=18845614}}</ref><ref name="UniProt"/> Release of the large dense core vesicles and the small synaptic vesicles is regulated differently. Neuropeptides are released in a calcium-dependent manner to bind to [[G protein-coupled receptor]](GPCRs)]]. Large dense core vesicles release low volumes of neuropeptide compared to synaptic vesicles and neurotransmitters. Neuropeptides are not immediately reuptaken, degraded or recycled and thus are bioactive for long periods of time.<ref name=":2" />
{{Unreferenced section|date=February 2024}}
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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. [[Crustacean Cardioactive Peptide|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.


== Synthesis ==
Peptidergic expression in the brain can be highly selective and specific. In ''Drosophila'' larvae for example, eclosion hormone is expressed in just two neurons and SIFamide is expressed in four.<ref name=":1" /> In contrast to its selective expression, peptidergic activity can be broad and long-lasting. Neuropeptides are often co-released with other peptides and traditional neurotransmitters. For example, vasoactive intestinal peptide is typically co-released with acetylcholine.<ref>{{Cite journal|last1=Dori|first1=I.|last2=Parnavelas|first2=J. G.|date=1989-07-01|title=The cholinergic innervation of the rat cerebral cortex shows two distinct phases in development|journal=Experimental Brain Research|language=en|volume=76|issue=2|pages=417–423|doi=10.1007/BF00247899|pmid=2767193|issn=1432-1106}}</ref>
Neuropeptides are synthesized from inactive [[Protein precursor|precursor proteins]] called prepropeptides.<ref name=":3">{{cite book | vauthors = Mains RE, Eipper BA |chapter=The Neuropeptides |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK28247/ |title=Basic Neurochemistry |date=1999 |publisher=Lippincott-Raven |isbn=978-0-397-51820-3 |edition=6th }}</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">{{cite journal | vauthors = Elphick MR, Mirabeau O, Larhammar D | title = Evolution of neuropeptide signalling systems | journal = The Journal of Experimental Biology | volume = 221 | issue = Pt 3 | pages = jeb151092 | date = February 2018 | pmid = 29440283 | pmc = 5818035 | doi = 10.1242/jeb.151092 }}</ref> In addition to the precursor peptide sequences, prepropeptides also contain a signal peptide, spacer peptides, and cleavage sites.<ref name=":6">{{Cite web|title=nEUROSTRESSPEP: Insect Neuropeptides|url=http://www.neurostresspep.eu/diner/insectneuropeptides|access-date=2021-08-25|website=www.neurostresspep.eu}}</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">{{cite journal | vauthors = Hökfelt T, Bartfai T, Bloom F | title = Neuropeptides: opportunities for drug discovery | journal = The Lancet. Neurology | volume = 2 | issue = 8 | pages = 463–472 | date = August 2003 | pmid = 12878434 | doi = 10.1016/S1474-4422(03)00482-4 | s2cid = 23326450 }}</ref><ref name=":5">{{cite journal | vauthors = Russo AF | title = Overview of Neuropeptides: Awakening the Senses? | journal = Headache | volume = 57 | issue = Suppl 2 | pages = 37–46 | date = May 2017 | pmid = 28485842 | pmc = 5424629 | doi = 10.1111/head.13084 }}</ref><ref name=":1">{{cite journal | vauthors = Nässel DR, Zandawala M | title = Recent advances in neuropeptide signaling in Drosophila, from genes to physiology and behavior | journal = Progress in Neurobiology | volume = 179 | pages = 101607 | date = August 2019 | pmid = 30905728 | doi = 10.1016/j.pneurobio.2019.02.003 | s2cid = 84846652 }}</ref>


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== Mechanism ==
In contrast to its selective expression, peptide action can be broad and diverse. Peptides bind to GPCRs to induce signaling cascades that alter cellular and synaptic activity. There is also tissue-specific processing of neuropeptide precursors. Different tissues have tailored post-translational processing steps which yield structurally and functionally different peptides.<ref name=":2" /> Peptides can affect gene expression, local blood flow, synaptogenesis and glial cell morphology. <br />
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">{{Cite book | vauthors = Mains RE, Eipper BA |date=1999 | chapter = The Neuropeptides | chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK28247/ | title = Basic Neurochemistry: Molecular, Cellular and Medical Aspects. 6th edition |publisher=Lippincott-Raven |language=en}}</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 receptor]]s (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">{{cite journal | vauthors = Dori I, Parnavelas JG | title = The cholinergic innervation of the rat cerebral cortex shows two distinct phases in development | journal = Experimental Brain Research | volume = 76 | issue = 2 | pages = 417–423 | date = July 1989 | pmid = 2767193 | doi = 10.1007/BF00247899 | s2cid = 19504097 }}</ref> Neuropeptide release can also be specific. In ''Drosophila'' larvae, for example, eclosion hormone is expressed in just two neurons.<ref name=":1" />


== Receptor targets ==
== Receptor targets ==
Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.<ref>{{Cite journal|last1=Brody|first1=Thomas|last2=Cravchik|first2=Anibal|date=2000-07-24|title=Drosophila melanogasterG Protein–Coupled Receptors|url=https://rupress.org/jcb/article/150/2/F83/47911/Drosophila-melanogasterG-Protein-Coupled-Receptors|journal=Journal of Cell Biology|language=en|volume=150|issue=2|pages=F83–F88|doi=10.1083/jcb.150.2.F83|pmid=10908591|pmc=2180217|issn=0021-9525}}</ref>  Most peptides activate a single GPCR, while some activate multiple GPCRs (e.g. AstA, AstC, DTK).<ref name=":0">{{Cite journal|last1=Nässel|first1=Dick R.|last2=Winther|first2=Åsa M. E.|date=2010-09-01|title=Drosophila neuropeptides in regulation of physiology and behavior|journal=Progress in Neurobiology|language=en|volume=92|issue=1|pages=42–104|doi=10.1016/j.pneurobio.2010.04.010|pmid=20447440|issn=0301-0082}}</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" />.
Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.<ref>{{cite journal | vauthors = Brody T, Cravchik A | title = Drosophila melanogaster G protein-coupled receptors | journal = The Journal of Cell Biology | volume = 150 | issue = 2 | pages = F83–F88 | date = July 2000 | pmid = 10908591 | pmc = 2180217 | doi = 10.1083/jcb.150.2.f83 }}</ref>  Most peptides activate a single GPCR, while some activate multiple GPCRs (e.g. AstA, AstC, DTK).<ref name=":0">{{cite journal | vauthors = Nässel DR, Winther AM | title = Drosophila neuropeptides in regulation of physiology and behavior | journal = Progress in Neurobiology | volume = 92 | issue = 1 | pages = 42–104 | date = September 2010 | pmid = 20447440 | doi = 10.1016/j.pneurobio.2010.04.010 | s2cid = 24350305 }}</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>{{Cite journal|last1=Dürrnagel|first1=Stefan|last2=Kuhn|first2=Anne|last3=Tsiairis|first3=Charisios D.|last4=Williamson|first4=Michael|last5=Kalbacher|first5=Hubert|last6=Grimmelikhuijzen|first6=Cornelis J. P.|last7=Holstein|first7=Thomas W.|last8=Gründer|first8=Stefan|date=2010-04-16|title=Three Homologous Subunits Form a High Affinity Peptide-gated Ion Channel in Hydra|journal=Journal of Biological Chemistry|language=en|volume=285|issue=16|pages=11958–11965|doi=10.1074/jbc.M109.059998|issn=0021-9258|pmid=20159980|pmc=2852933}}</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>{{Cite journal|last1=Chang|first1=Jer-Cherng|last2=Yang|first2=Ruey-Bing|last3=Adams|first3=Michael E.|last4=Lu|first4=Kuang-Hui|date=2009-08-11|title=Receptor guanylyl cyclases in Inka cells targeted by eclosion hormone|journal=Proceedings of the National Academy of Sciences|language=en|volume=106|issue=32|pages=13371–13376|doi=10.1073/pnas.0812593106|issn=0027-8424|pmid=19666575|pmc=2726410|bibcode=2009PNAS..10613371C}}</ref>
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>{{cite journal | vauthors = Dürrnagel S, Kuhn A, Tsiairis CD, Williamson M, Kalbacher H, Grimmelikhuijzen CJ, Holstein TW, Gründer S | display-authors = 6 | title = Three homologous subunits form a high affinity peptide-gated ion channel in Hydra | journal = The Journal of Biological Chemistry | volume = 285 | issue = 16 | pages = 11958–11965 | date = April 2010 | pmid = 20159980 | pmc = 2852933 | doi = 10.1074/jbc.M109.059998 | doi-access = free }}</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>{{cite journal | vauthors = Chang JC, Yang RB, Adams ME, Lu KH | title = Receptor guanylyl cyclases in Inka cells targeted by eclosion hormone | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 106 | issue = 32 | pages = 13371–13376 | date = August 2009 | pmid = 19666575 | pmc = 2726410 | doi = 10.1073/pnas.0812593106 | doi-access = free | bibcode = 2009PNAS..10613371C }}</ref>


== Examples ==
== Actions ==
Due to their modulatory and diffusive nature, neuropeptides can act on multiple time and spatial scales. Below are some examples of neuropeptide actions:
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 [[gamma-Aminobutyric acid|GABA]].


=== Corelease ===
Invertebrates also have many neuropeptides. [[Crustacean Cardioactive Peptide|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.
Neuropeptides are often co-released with other neurotransmitters and neuropeptides to modulate synaptic activity. [[Synaptic vesicle]]s and dense core vesicles can have differential activation properties for release, resulting in context-dependent corelease combinations.<ref>{{cite journal | vauthors = Nässel DR | title = Substrates for Neuronal Cotransmission With Neuropeptides and Small Molecule Neurotransmitters in ''Drosophila'' | journal = Frontiers in Cellular Neuroscience | volume = 12 | pages = 83 | date = 2018-03-23 | pmid = 29651236 | pmc = 5885757 | doi = 10.3389/fncel.2018.00083 | doi-access = free }}</ref><ref>{{cite journal | vauthors = van den Pol AN | title = Neuropeptide transmission in brain circuits | journal = Neuron | volume = 76 | issue = 1 | pages = 98–115 | date = October 2012 | pmid = 23040809 | pmc = 3918222 | doi = 10.1016/j.neuron.2012.09.014 }}</ref><ref>{{cite journal | vauthors = Nusbaum MP, Blitz DM, Swensen AM, Wood D, Marder E | title = The roles of co-transmission in neural network modulation | language = English | journal = Trends in Neurosciences | volume = 24 | issue = 3 | pages = 146–154 | date = March 2001 | pmid = 11182454 | doi = 10.1016/S0166-2236(00)01723-9 | s2cid = 8994646 }}</ref> For example, insect [[motor neuron]]s 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>{{cite journal | vauthors = Adams ME, O'Shea M | title = Peptide cotransmitter at a neuromuscular junction | journal = Science | volume = 221 | issue = 4607 | pages = 286–289 | date = July 1983 | pmid = 6134339 | doi = 10.1126/science.6134339 | bibcode = 1983Sci...221..286A }}</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>{{Cite web|title=The Nobel Prize in Physiology or Medicine 1977|url=https://www.nobelprize.org/prizes/medicine/1977/press-release/|access-date=2021-12-15|website=NobelPrize.org|language=en-US}}</ref><ref>{{cite journal | vauthors = Childs GV, Westlund KN, Tibolt RE, Lloyd JM | title = Hypothalamic regulatory peptides and their receptors: cytochemical studies of their role in regulation at the adenohypophyseal level | journal = Journal of Electron Microscopy Technique | volume = 19 | issue = 1 | pages = 21–41 | date = September 1991 | pmid = 1660066 | doi = 10.1002/jemt.1060190104 }}</ref> 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).<ref>{{cite journal | vauthors = Lau J, Farzi A, Qi Y, Heilbronn R, Mietzsch M, Shi YC, Herzog H | title = CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis | journal = Molecular Metabolism | volume = 7 | pages = 102–118 | date = January 2018 | pmid = 29146410 | pmc = 5784325 | doi = 10.1016/j.molmet.2017.10.015 }}</ref> These peptides are all released in different combinations to signal hunger and satiation cues.<ref>{{cite journal | vauthors = Luckman SM, Lawrence CB | title = Anorectic brainstem peptides: more pieces to the puzzle | journal = Trends in Endocrinology and Metabolism | volume = 14 | issue = 2 | pages = 60–65 | date = March 2003 | pmid = 12591175 | doi = 10.1016/S1043-2760(02)00033-4 | s2cid = 25055675 }}</ref>
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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.

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


'''[[Norepinephrine]]''' (noradrenaline).
'''[[Norepinephrine]]''' (noradrenaline).
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Some neurons make several different peptides. For instance,
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 [[Corticotropin-releasing hormone|CRF]] (in parvocellular neurons of the [[paraventricular nucleus]])
[[vasopressin]] co-exists with [[dynorphin]] and [[galanin]] in magnocellular neurons of the [[supraoptic nucleus]] and [[paraventricular nucleus]], and with [[Corticotropin-releasing hormone|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]].
[[Oxytocin]] in the [[supraoptic nucleus]] co-exists with [[enkephalin]], [[dynorphin]], [[cocaine-and amphetamine regulated transcript]] (CART) and [[cholecystokinin]].

== Evolution of Neuropeptide Signaling ==
[[Peptide]]s are ancient signaling systems that are found in almost all animals on Earth.<ref name=":2">{{cite journal | vauthors = Schoofs L, De Loof A, Van Hiel MB | title = Neuropeptides as Regulators of Behavior in Insects | journal = Annual Review of Entomology | volume = 62 | pages = 35–52 | date = January 2017 | pmid = 27813667 | doi = 10.1146/annurev-ento-031616-035500 | url = https://lirias.kuleuven.be/handle/123456789/632231 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Jékely G | title = The chemical brain hypothesis for the origin of nervous systems | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 376 | issue = 1821 | pages = 20190761 | date = March 2021 | pmid = 33550946 | doi = 10.1098/rstb.2019.0761 | pmc = 7935135 }}</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>{{cite journal | vauthors = Sachkova MY, Nordmann EL, Soto-Àngel JJ, Meeda Y, Górski B, Naumann B, Dondorp D, Chatzigeorgiou M, Kittelmann M, Burkhardt P | display-authors = 6 | title = Neuropeptide repertoire and 3D anatomy of the ctenophore nervous system | journal = Current Biology | volume = 31 | issue = 23 | pages = 5274–5285.e6 | date = December 2021 | pmid = 34587474 | doi = 10.1016/j.cub.2021.09.005 | s2cid = 238210404 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Takahashi T, Takeda N | title = Insight into the molecular and functional diversity of cnidarian neuropeptides | journal = International Journal of Molecular Sciences | volume = 16 | issue = 2 | pages = 2610–2625 | date = January 2015 | pmid = 25625515 | pmc = 4346854 | doi = 10.3390/ijms16022610 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Mirabeau O, Joly JS | title = Molecular evolution of peptidergic signaling systems in bilaterians | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 110 | issue = 22 | pages = E2028–E2037 | date = May 2013 | pmid = 23671109 | pmc = 3670399 | doi = 10.1073/pnas.1219956110 | bibcode = 2013PNAS..110E2028M | doi-access = free }}</ref><ref name="Evolution of neuropeptide signallin"/> Recent studies also show genomic evidence of neuropeptide processing machinery in metazoans and [[choanoflagellate]]s, suggesting that neuropeptide signaling may predate the development of nervous tissues.<ref>{{cite journal | vauthors = Yañez-Guerra LA, Thiel D, Jékely G | title = Premetazoan Origin of Neuropeptide Signaling | journal = Molecular Biology and Evolution | volume = 39 | issue = 4 | pages = msac051 | date = April 2022 | pmid = 35277960 | doi = 10.1093/molbev/msac051 | pmc = 9004410 }}</ref> Additionally, [[Ctenophora|Ctenophore]] and [[Placozoa]] neural signaling is entirely peptidergic and lacks the major amine [[neurotransmitter]]s such as acetylcholine, dopamine, and serotonin.<ref>{{cite journal | vauthors = Varoqueaux F, Williams EA, Grandemange S, Truscello L, Kamm K, Schierwater B, Jékely G, Fasshauer D | display-authors = 6 | title = High Cell Diversity and Complex Peptidergic Signaling Underlie Placozoan Behavior | journal = Current Biology | volume = 28 | issue = 21 | pages = 3495–3501.e2 | date = November 2018 | pmid = 30344118 | doi = 10.1016/j.cub.2018.08.067 | s2cid = 53044824 | doi-access = free }}</ref><ref name=":2" /> This also suggests that neuropeptide signaling developed before amine neurotransmitters.

== 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">{{cite journal |vauthors=V Euler US, Gaddum JH |date=June 1931 |title=An unidentified depressor substance in certain tissue extracts |journal=The Journal of Physiology |volume=72 |issue=1 |pages=74–87 |doi=10.1113/jphysiol.1931.sp002763 |pmc=1403098 |pmid=16994201}}</ref><ref name=":9" />

In insects, [[proctolin]] was the first neuropeptide to be isolated and sequenced.<ref>{{cite book |doi=10.1016/B978-012369442-3/50030-1 |chapter=Proctolin in Insects |title=Handbook of Biologically Active Peptides |year=2006 | vauthors = Lange AB, Orchard I |pages=177–181 |isbn=9780123694423 }}</ref><ref>{{cite journal | vauthors = Starratt AN, Brown BE | title = Structure of the pentapeptide proctolin, a proposed neurotransmitter in insects | journal = Life Sciences | volume = 17 | issue = 8 | pages = 1253–1256 | date = October 1975 | pmid = 576 | doi = 10.1016/0024-3205(75)90134-4 }}</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>{{cite book |doi=10.1016/B978-0-12-801028-0.00067-2 |chapter=Proctolin |title=Handbook of Hormones |year=2016 | vauthors = Tanaka Y |isbn=9780128010280 }}</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 ==
== References ==
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== External links ==
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* [https://www.journals.elsevier.com/neuropeptides ''Neuropeptides'' Journal]
* [https://www.journals.elsevier.com/neuropeptides ''Neuropeptides'' Journal]
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[[Category:Molecular biology]]
[[Category:Molecular biology]]

Latest revision as of 13:08, 8 July 2024

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 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

[edit]

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.

Synthesis

[edit]

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]

Mechanism

[edit]

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 G protein-coupled receptors (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]

Receptor targets

[edit]

Most neuropeptides act on G-protein coupled receptors (GPCRs). Neuropeptide-GPCRs fall into two families: rhodopsin-like and the secretin class.[10]  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.[11] 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.[12]

Actions

[edit]

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

Corelease

[edit]

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.[13][14][15] 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.[16] 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[17][18] 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).[19] These peptides are all released in different combinations to signal hunger and satiation cues.[20]

The following is a list of neuroactive peptides cor-eleased 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.

Evolution of Neuropeptide Signaling

[edit]

Peptides are ancient signaling systems that are found in almost all animals on Earth.[21][22] Genome sequencing reveals evidence of neuropeptide genes in Cnidaria, Ctenophora, and Placozoa, some of oldest living animals with nervous systems or neural-like tissues.[23][24][25][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.[26] Additionally, Ctenophore and Placozoa neural signaling is entirely peptidergic and lacks the major amine neurotransmitters such as acetylcholine, dopamine, and serotonin.[27][21] This also suggests that neuropeptide signaling developed before amine neurotransmitters.

Research history

[edit]

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. [28][9]

In insects, proctolin was the first neuropeptide to be isolated and sequenced.[29][30] 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.[31]

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

References

[edit]
  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". www.neurostresspep.eu. 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. ^ 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.
  11. ^ 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.
  12. ^ 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.
  13. ^ 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.
  14. ^ 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.
  15. ^ 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.
  16. ^ 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.
  17. ^ "The Nobel Prize in Physiology or Medicine 1977". NobelPrize.org. Retrieved 15 December 2021.
  18. ^ 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.
  19. ^ 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.
  20. ^ 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.
  21. ^ 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.
  22. ^ 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.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ 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.
  27. ^ 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.
  28. ^ 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.
  29. ^ 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.
  30. ^ 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.
  31. ^ Tanaka Y (2016). "Proctolin". Handbook of Hormones. doi:10.1016/B978-0-12-801028-0.00067-2. ISBN 9780128010280.
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