Neuropeptide

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]

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]

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]

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]

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:

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][34] 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.[35] Additionally, Ctenophore and Placozoa neural signaling is entirely peptidergic and lacks the major amine neurotransmitters such as acetylcholine, dopamine, and serotonin.[36][29] 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.

Look up neuropeptide in Wiktionary, the free dictionary.

• 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