Extrasynaptic exocytosis and its mechanisms: a source of molecules mediating volume transmission in the nervous system

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.

Keywords: exocytosis; extrasynaptic; mechanisms of extrasynaptic exocytosis; serotonin; somatic exocytosis; volume transmission.

Figure 1

Schematic representation of extrasynaptic and synaptic exocytosis from clear and dense core vesicles in different regions of serotonergic neurons. (A) Mechanism of long-lasting somatic secretion from dense core vesicles in leech Retzius neurons. Electrical stimulation of neurons with trains of 10–20 Hz produces transmembrane calcium entry through L type channels (LCach). This calcium in turn activates calcium-induced calcium release from progressively more internal endoplasmic reticulum stores (er). Calcium waves propagate to internal regions of the soma and activate ATP synthesis by the mithocondria (mit). The ATP increase activates kinesin motors (km) that transport dense core vesicle clusters (dcvc) along microtubule rails (mt) towards the plasma membrane (pm), with which they fuse. This exocytosis lasts for minutes after the end of the train of electrical activity. Serotonin is released onto glial cells. (B) Hypothetical model of serotonin release from axonal varicosities containing clear and/or dense core vesicles. Both vesicle types may contain serotonin, as in serotonergic raphe neurons, and at rest lay at nanometer distances from the plasma membrane. In these cases exocytosis occurs in the absence of a postsynaptic counterpart and serotonin activates extrasynaptic receptors (esr). It is expected that with this configuration single impulses or low frequency trains do not evoke significant amounts of exocytosis although they contribute to approaching vesicles toward the plasma membrane, thus increasing the probability of release upon subsequent impulses. At high frequencies, both vesicle pools increase their fusion probability. The vesicles with white centers represent those during or after exocytosis (C) Synaptic and extrasynaptic exocytosis from synaptic bouttons. Clear vesicles at presynaptic endings are apposed to the plasma membrane and single impulses evoke exocytosis with mechanisms similar to those in neuromuscular junction. Dense core vesicles surrounding clear vesicles have low release probability and subsequent impulses increase the probability of exocytosis. At high frequencies, the clear vesicle pool enters the facilitation/depression dynamics, whereas the dense core vesicle pool increases its release probability. While clear vesicle contents are released onto the synaptic cleft and affect mostly synaptic receptors (sr), dense core vesicles release their contents extrasynaptically and serotonin activates extrasynaptic receptors (esr). For additional details and references see the text.