By far the most numerous class of neuroactive species are the neuropeptides. There are between one and two dozen small-molecule neurotransmitters, mostly synthesized from 4 or 5 amino acids (excepting ACh, for which the essential nutrient choline is the precursor), but there are over a hundred confirmed neuropeptides which range from four to over 50 amino acid residues in length.
At least 90 genes are known to code for neuropeptides. Synthesis of neuropeptides occurs in the ER where large precursor peptides (prohormones) are translated into the lumen of the ER. Differential processing of these precursors often results in several related neuropeptides with different or overlapping sequences. In the trans-Golgi network these peptides are packaged into vesicles which are transported to the axon terminal and elsewhere in the cell. Because neuropeptides are synthesized as gene products and packed into vesicles during synthesis they cannot be rapidly recycled or replenished as are amino acids or catecholamines. Neuropeptides are secreted at axon terminals, and likely elsewhere in the neural soma and along its many projections.
Generally, receptors for neuropeptides in the CNS and the periphery are GPCRs which are found in heterogeneous distributions in the soma, dentridic branches, and axon terminals. This points to the neuromodulatory role that may be played by neuropeptides. GPCR receptors for many neuropeptides form both homo-and-hetero dimers leading to a large variety of cross-reactivity, especially for families of closely-related neuropeptides such as the endogenous opioids (e.g. β- endorphin, enkephalin, dynorphin).
While oxytocin and a few other neuropeptides which are secreted at high concentrations seem have systematic activity as neurohormones, most neuropeptides are secreted in much lower total abundance and appear to have extracellular concentrations between 1 pM and 1 nM. This is in contrast to small molecule volume neurotransmitters like dopamine which may have concentration in the extracellular space ranging from 100 nM to 1 µM. The low levels of peptide, combined with the specific localization of neuropeptide receptors also points to the action of neuropeptides as being volume neurotransmitters or neuromodulators. While much evidence points of diffuse, low-frequency action of neuropeptides, this perspective may in part be due to the fact that dynamic in vivo monitoring of neuropeptides has not yet achieved the spatial or temporal resolution that has been attained by electrophysiological monitoring of ACh or amino acid synaptic transmission, or the electrochemical measurements of catecholamines and serotonin.
What is clear is that neuropeptides play diverse and important roles in the chemical communication of the nervous system: several neuropeptides show 95-100% sequence homology across the animal kingdoms, and are essential to survival. One example is pituitary adenylate cyclase activating polypeptide (PACAP): a 38 residue neuropeptide with 100% sequence conservation in mammals. Knockout of the PACAP gene leads to an inviable fetus because the peptide plays a crucial role in differentiation and migration of neuronal stem cells in addition to many other roles.
The measurement of neuropeptides continues to expand, especially as mass spectrometry analysis of peptides collected in vivo and post mortem has allowed sensitive detection with selective identification. The genes for nearly all GPCRs have been identified and localized in many tissues. However many of these receptors do not have known endogenous ligands. Could some of these GPCRs be associated with yet unknown or uncharacterized neuropeptides? Are all the neuropeptides identified truly important as neuroactive signaling molecules, or are many vestigial products of redundant or evolutionally defunct genes? Neuroscientists are working to discover the answers using genetic, microbiology, and in vivo chemical measurements. The complexity of this field is sure to stimulate many exciting research discoveries and occupy scientists for some time.
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