Neuropeptide

Neuropeptides are "peptides released by neurons as intercellular messengers. Many neuropeptides are also hormones released by non-neuronal cells." In general, neuropeptides are synthesised as part of a much larger precursor molecule which is then cleaved enzymatically to yield various peptide fragments. In neurons, neuropeptides are generally packaged within large neurosecretory vesicles, that may be found in any region of the neuron - soma, dendrites, axons and nerve endings. The vesicle contents are released into the extracellular fluid when the vesicle membrane fuses with the neuronal plasma membrane in a process of calcium-dependent exocytosis. For example, vasopressin is made by magnocellular neurons in the supraoptic nucleus and paraventricular nucleus of the hypothalamus; it is a nine-amino acid fragment of a large (~30kD) precursor molecule which is packaged into large membrane-bound vesicles that are transported to all parts of the cell but especially to the neurosecretory nerve endings in the posterior pituitary gland. During transport, the precursor molecule is cleaved to yield a signal peptide, vasopressin, vasopressin-related neurophysin (neurophysin II), and a glycoprotein. The glycoprotein has no known function; neurophysin is important for the correct folding of the precursor hormone to allow it to be packaged in vesicles. Each vesicle contains about 85,000 molecules of vasopressin; as vasopressin is active at its receptors in sub nanomolar concentrations, this is a very potent cargo indeed.

Most neurons make at least one peptide in addition to a conventional neurotransmitter (such as glutamate, GABA or dopamine), but the peptide and transmitter are not generally present in the same vesicles. Neurotransmitters are packeged in small synaptic vesicles that are selectively targetted to nerve endings, whereas neuropeptides can be released from any part of a neuron. Many neurons make several different peptides. For example, one population of apetite-regulating neurons in the arcuate nucleus of the hypothalamus makes at least two peptides - neuropeptide Y and agouti-related peptide - and uses GABA as a conventional neurotransmitter.

Types of neuropeptides

More than 100 different peptides have been shown to be expressed by different subpopulations of neurons in the CNS. Amongst them are the hypothalamic releasing hormones that control secretion of hormones from the anterior pituitary gland; for example, somatostatin is made in many neurons, including in interneurons in the hippocampus, but is also released from the neurosecretory nerve endings of neuroendocrine neurons in the periventricular nucleus of the hypothalamus to inhibit the secretion of growth hormone, while another population of neuroendocrine neurons in the arcuate nucleus of the hypothalamus synthesises and releases growth hormone releasing hormone which stimulates the secretion of growth hormone.

Amongst the best known and most widely distributed families of neuropeptides are the endogenous opioids: the dynorphins, the endorphins, the enkephalins and nociceptin. Once thought to be specifically involved in modulating pain, these are now known to have a very wide variety of important roles in many different neural systems.

Many neuropeptides have specific roles in particular behaviors or physiological functions, but often their names are misleading. For example, orexin was named because of its apparent ability to stimulate eating, but is now recognised as having its major role in arousal mechanisms. Conversely, important appetite regulating neuropeptides include alpha melanocyte stimulating hormone, melanin concentrating hormone, cocaine and amphetamine related transcript, agouti related peptide and prolactin releasing peptide. Vasoactive intestinal peptide, released by neurons of the suprachiasmatic nucleus is a major controller of circadian rhythms. Generally these peptides were first descovered in the periphery, and named after their apparent actions there, before being recognised as also being neuropeptides.

Typically, peptides act via binding to specific G-protein coupled receptors that are expressed on the surface of target cells (thoufgh some act via receptor tyrosine kinases). There can be several different receptors through which any one neuropeptide might act; vasopressin for example signals through three known receptors - V1a, V1b and V2 receptors.

Receptors for a neuropeptide may be expressed by the neuron that makes that peptide - these are called "autoreceptors" and they generally mediate negative-feedback control of cell activity. For example, neuropeptide Y signals back to its cells of origin via Y2 autoreceptors. Often receptors are expressed on different neurons, but sometimes on glial cells or on endothelial cells, via which they can regulate local blood flow.

The actions of neuropeptides are very diverse; some have genomic effects, on gene expression in target cells, others have effects on membrane excitability ("neuromodulators"), others still are growth factors. Some peptides influence synaptogenesis, and glial cell morphology.

Neuropeptides tend to have prolonged actions; in the brain, they are metabolised by various endopeptidases but often have half lives of several minutes. The same neuropeptide may have many different functions, depending on the functions of the different neurons that may all express it, and depending on the different roles of the various cells on which it acts. For example, vasopressin was so named because of its hormonal actions on blood vessels that mediate its effects on blood pressure, but its more important physiological role is exerted through Y2 receptors at the kidney, as the antidiuretic hormone. In these cases, the vasopressin that has these effects is released from the posterior pituitary gland, by the nerve endings of magnocellular neuroendocrine cells. The same neurons release vasopressin from their dendrites, where it acts back on those same cells via V1 receptors as a feedback regulator of cellular activity. Vasopressin is also however released from parvocellular neurosecretory cells of the paraventricular nucleus as a secretagogue for adrenocorticotropic hormone]] from the anterior pituitary gland. In addition, it is released from centrally projecting neurons with diverse effects, including in temperature regulation, neurogenic regulation of blood pressure, and in the regulation of aggression and social behavior.

C.elegans

Neuropeptides are a major signalling system in all animals. The sequencing of the C. elegans genome resulted in the identification of 113 neuropeptide genes encoding over 250 distinct neuropeptides. As in mammals, C. elegans neuropeptides are derived from precursor molecules that must be post-translationally processed to yield the active peptides. The neuropeptide genes are found throughout the nervous system, including in sensory neurons, motor neurons, and interneurons; these neuropeptides appear to have a modulatory role in many, if not all, behaviors shown by C. elegans. Some of these neuropeptides are found only in invertebrates but many have mammalian homologues.