Journal of the Autonomic Nervous System
Modulation of fast synaptic transmission by presynaptic ligand-gated cation channels
Introduction
Synaptic transmission in the nervous system is achieved by the rapid exocytosis of neurotransmitter from specialized presynaptic elements. Upon release the neurotransmitter diffuses across the synaptic cleft to activate postsynaptic receptors. The amount and duration of neurotransmitter release is controlled by multiple, interacting processes (Neher, 1998, Benfenati et al., 1999). One important mechanism by which neurotransmitter release can be modulated is by receptors located on the presynaptic membrane. These can be either autoreceptors (i.e., activated by the neurotransmitter released at that synapse) or heteroreceptors (i.e., activated by substances released from other neuronal or non-neuronal elements). Until recently the most extensively studied types of presynaptic receptors were the G-protein-coupled seven transmembrane domain receptors (Langer, 1997, Miller, 1999) and the GABA- or glycine-activated ligand-gated anion channels (MacDermott et al., 1999). There is now considerable evidence demonstrating that ligand-gated cation channels (e.g., P2X, nicotinic, kainate, NMDA, AMPA and 5-HT3 receptors) also exist on nerve terminals where they function to modulate neurotransmitter release (McGehee and Role, 1996, MacDermott et al., 1999). Thus ligand-gated cation channels are not only located postsynaptically to mediate fast synaptic transmission but also presynaptically to modulate neurotransmitter release.
In this review we shall focus on recent electrophysiological studies of the modulation by presynaptic ligand-gated cation channels of both spontaneous and evoked neurotransmitter release and illustrate the complexity of this modulation which can be both multimodal and bi-directional. Before discussing responses mediated by individual classes of ligand-gated ion channels, we shall review the mechanisms by which presynaptic ligand-gated cation channels can modify neurotransmitter release. The complexity of these mechanisms is compounded by the varying distribution of ligand-gated cation channels along the nerve fibre where they may be remote from the neurotransmitter release site (sometimes referred to as ‘preterminal’) or close to the release site (sometimes referred to as ‘terminal’).
Section snippets
Modulation of spontaneous neurotransmitter release
Neurotransmitters can be released spontaneously from presynaptic nerves following the firing of a spontaneous action potential in the nerve terminal or, in the absence of action potential firing, by spontaneous fusion of the synaptic vesicle with the plasma membrane resulting in exocytosis. The study of spontaneous synaptic events permits determination of the location of the ligand-gated cation channels (i.e., presynaptic or postsynaptic). A requirement that a particular receptor produces an
Modulation of evoked neurotransmitter release
Although it may seem intuitive that activation of ligand-gated cation channels should enhance the release of neurotransmitters evoked by nerve stimulation, this view is somewhat simplistic. First, an enhancement of neurotransmitter release may not be seen simply as an increase in evoked release, but may be observed as a more subtle enhancement in which there is a decrease in the number of occasions in which an evoked action potential fails to evoke release (i.e., a decrease in the rate of
P2X receptors
Given that this volume is in honour of the scientific contributions of Professor Geoffrey Burnstock it is entirely appropriate that, when focussing on individual receptor types, we start with P2X receptors. P2X receptors are ATP-gated non-selective cation channels that are permeable to sodium, potassium and Ca2+ ions (Burnstock, 1996, North and Barnard, 1997, Rogers et al., 1997). Seven P2X subunits are known to exist (P2X1–P2X7) (Ralevic and Burnstock, 1998), and most of these can form both
Ionotropic glutamate receptors
Glutamate is the major fast excitatory neurotransmitter in the brain and once released it acts on kainate, NMDA or AMPA ligand-gated cation channels. Each of these receptors has also been reported to be expressed on nerve terminals and to modify both spontaneous and evoked release of both excitatory, including glutamate itself, and inhibitory neurotransmitters.
Summary
The classical view of ligand-gated ion channels is as postsynaptic mediators of fast synaptic responses. However, the work discussed here demonstrates that they may also have an important presynaptic role in the modulation of synaptic transmission. The predominant effect of presynaptic ligand-gated cation channel activation on spontaneous neurotransmitter release is enhancement of the frequency of release (see Table 1), and this appears to be common to all types of ligand-gated cation channels.
Acknowledgements
Thanks to Drs. Elizabeth Seward and Cesar Labarca for comments on the manuscript.
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