Trends in Neurosciences
Presynaptic inhibition of elicited neurotransmitter release
Section snippets
Relationship between neurotransmitter release and presynaptic Ca2+ concentration
Understanding the relationship between transmitter release and presynaptic Ca2+ influx is essential to quantifying the contribution of a decrease in Ca2+ influx to inhibition of elicited release. Early studies found that the amplitude of the postsynaptic potential has an extremely steep dependence on extracellular Ca2+ concentration, approximating a third- to fourth-power function in both frog neuromuscular junction[18] and squid giant synapse[19]. Co-operativity of intracellular Ca2+ ions to
Multiple types of Ca2+ channels in presynaptic terminals
Biophysical and pharmacological analyses have led to the description of several classes of voltage-dependent Ca2+ currents, usually referred to as L-, N-, T-, P-, Q- and R-type currents (for a review, see [34]). Several pharmacological tools are useful in identifying these currents (see 34, 35 for more detail). In general, L-type currents are blocked by dihydropyridine antagonists, N-type by v-conotoxin GVIA (v-CgTx GVIA), P-type by lower concentrations of v-agatoxin IVA (v-Aga IVA; Kd ~1–3nm)35
Inhibition of presynaptic Ca2+ influx
Since the first paper describing an inhibition of somatic Ca2+ action potentials by neurotransmitters[47] there have been numerous reports of somatic Ca2+ spikes and, in recent years, of somatic Ca2+ currents that are blocked by presynaptic modulators, often via a G protein-mediated pathway (for example, 48, 49, 50, 51, 52, 53, 54, 55; for reviews, see 2, 5, 56). These findings have been taken as indirect evidence for the involvement of Ca2+ channels in presynaptic inhibition. Consistent with
Differential inhibition of multiple types of Ca2+ channels
The evidence suggesting that suppression of the presynaptic Ca2+ influx is due to inhibition of Ca2+ channels rather than activation of K+ channels arises mainly from the differential effect of presynaptic modulators on pharmacologically distinct components of Ca2+ influx (Table 1). These results were revealed by the differential occlusion between specific Ca2+-channel blockers and presynaptic modulators on presynaptic Ca2+ influx. At hippocampal CA3–CA1 synapses, adenosine, baclofen and
Inhibition of spontaneous release by mechanisms downstream of Ca2+ entry
It was found that presynaptic receptor agonists, such as adenosine, baclofen and carbachol (a muscarinic-receptor agonist), reduce the frequency of miniature EPSCs (mEPSCs) without affecting the distribution of their amplitudes in hippocampal and cerebellar synapses and neuromuscular junctions7, 8, 9, 10, 15, 69. However, decreasing the elicited presynaptic Ca2+ influx by application of the Ca2+-channel blocker cadmium or a Ca2+-free solution does not affect the frequency of spontaneous release7
Concluding remarks
Recent evidence from different synapses and species suggest that presynaptic inhibition of elicited transmitter release is mainly due to a reduction of presynaptic Ca2+ influx through specific Ca2+-channel types (Table 1). At many synapses, elicited release is controlled by multiple types of Ca2+ channels, which are differentially affected by presynaptic modulators. The effect of modulation of Ca2+ channels on elicited release is amplified by the highly non-linear relationship between elicited
Acknowledgements
This work was supported by the National Institute of Health, Grant NS 33147 to PS. We thank J. Qian, S.R. Sinha, J.G.G. Borst, J. Angelson and F. Helmchen for critical and helpful comments on the manuscript.
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