Peptidergic transmission: from morphological correlates to functional implications.

Like non-peptidergic transmitters, neuropeptides and their receptors display a wide distribution in specific cell types of the nervous system. The peptides are synthesized, typically as part of a larger precursor molecule, on the rough endoplasmic reticulum in the cell body. In the trans-Golgi network, they are sorted to the regulated secretory pathway, packaged into so-called large dense-core vesicles, and concentrated. Large dense-core vesicles are preferentially located at sites distant from active zones of synapses. Exocytosis may occur not only at synaptic specializations in axonal terminals but frequently also at nonsynaptic release sites throughout the neuron. Large dense-core vesicles are distinguished from small, clear synaptic vesicles, which contain "classical' transmitters, by their morphological appearance and, partially, their biochemical composition, the mode of stimulation required for release, the type of calcium channels involved in the exocytotic process, and the time course of recovery after stimulation. The frequently observed "diffuse' release of neuropeptides and their occurrence also in areas distant to release sites is paralleled by the existence of pronounced peptide-peptide receptor mismatches found at the light microscopic and ultrastructural level. Coexistence of neuropeptides with other peptidergic and non-peptidergic substances within the same neuron or even within the same vesicle has been established for numerous neuronal systems. In addition to exerting excitatory and inhibitory transmitter-like effects and modulating the release of other neuroactive substances in the nervous system, several neuropeptides are involved in the regulation of neuronal development.