Abstract
We review the evidence of exocytosis from extrasynaptic sites in the soma, dendrites, and axonal varicosities of central and peripheral neurons of vertebrates and invertebrates, with emphasis on somatic exocytosis, and how it contributes to signaling in the nervous system. The finding of secretory vesicles in extrasynaptic sites of neurons, the presence of signaling molecules (namely transmitters or peptides) in the extracellular space outside synaptic clefts, and the mismatch between exocytosis sites and the location of receptors for these molecules in neurons and glial cells, have long suggested that in addition to synaptic communication, transmitters are released, and act extrasynaptically. The catalog of these molecules includes low molecular weight transmitters such as monoamines, acetylcholine, glutamate, gama-aminobutiric acid (GABA), adenosine-5-triphosphate (ATP), and a list of peptides including substance P, brain-derived neurotrophic factor (BDNF), and oxytocin. By comparing the mechanisms of extrasynaptic exocytosis of different signaling molecules by various neuron types we show that it is a widespread mechanism for communication in the nervous system that uses certain common mechanisms, which are different from those of synaptic exocytosis but similar to those of exocytosis from excitable endocrine cells. Somatic exocytosis has been measured directly in different neuron types. It starts after high-frequency electrical activity or long experimental depolarizations and may continue for several minutes after the end of stimulation. Activation of L-type calcium channels, calcium release from intracellular stores and vesicle transport towards the plasma membrane couple excitation and exocytosis from small clear or large dense core vesicles in release sites lacking postsynaptic counterparts. The presence of synaptic and extrasynaptic exocytosis endows individual neurons with a wide variety of time- and space-dependent communication possibilities. Extrasynaptic exocytosis may be the major source of signaling molecules producing volume transmission and by doing so may be part of a long duration signaling mode in the nervous system.
Highlights
Communication in the nervous system is classically known to occur at synapses, where a neurotransmitter released from the presynaptic active zone reaches the postsynaptic membrane and produces a local synaptic potential
This frequency dependence and the latency of exocytosis can be explained in terms of a highly regulated secretion process that requires the active transport of vesicles toward the plasma membrane in response to electrical stimulation and, as result of this, high energy expenses (De-Miguel et al, in press)
Dopaminergic amacrine cells release dopamine by exocytosis from the cell body (Puopolo et al, 2001) depending on the cell’s electrical activity. This exocytosis is mediated by calcium entry though L-type channels, modulated by glutamate and gama-aminobutiric acid (GABA) and auto-inhibited by dopamine through D2 receptors (Puopolo et al, 2001), with this last effect being similar to its autoinhibitory effects in the substantia nigra and striatum (Cobb and Abercrombie, 2003)
Summary
Communication in the nervous system is classically known to occur at synapses, where a neurotransmitter released from the presynaptic active zone reaches the postsynaptic membrane and produces a local synaptic potential. In the past fifteen years a variety of studies applying diverse techniques have provided direct evidence that serotonin, dopamine, noradrenaline, adenosine-5-triphosphate (ATP), and peptides such as substance P, brain-derived neurotrophic factor (BDNF), or oxytocin, are released by exocytosis from extrasynaptic sites by central and peripheral neurons of invertebrates and vertebrates These molecules activate mainly metabotropic receptors that exert indirect and slower effects than those of synaptic transmitters acting on ionotropic receptors. In brain areas with dense serotonergic innervation (Kaushalya et al, 2008b) All this morphological evidence suggests that serotonin is released from presynaptic terminals, and from extrasynaptic sites in axons, dendrites, and somata. Somatic dense core vesicles at rest are located in two pools: one around the nucleus and another in more peripheral areas of the cytoplasm, distant from the www.frontiersin.org
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