Release and the Resistant Channel

Abstract

Several subtypes of voltage-gated calcium channels that differ in their biophysical properties and pharmacological sensitivities have been identified. The N-, P/Q-, and R- subtypes can all mediate calcium influx into presynaptic nerve terminals. N- and P/Q-type channels play key roles in mediating evoked neurotransmitter release; the function of presynaptic R-type channels, however, has remained obscure. Dietrich et al. used a combination of pharmacological, electrophysiological, and genetic techniques to show that, at adult mouse hippocampal mossy fiber synapses, Cav2.3 channels (molecularly identified channels that contribute to R-type calcium current) selectively contribute to specific forms of calcium-dependent plasticity of neurotransmitter release. Electrophysiological analysis of evoked release to solitary action potentials, or in response to various stimulus paradigms, showed that Cav2.3 knockout or pharmacological blockade of R-type channels (using SNX-482 or low concentrations of nickel) selectively inhibited long-term potentiation and posttetanic potentiation of transmitter release, which depend on high-frequency stimulation. Baseline release, paired-pulse facilitation (which occurs after a single conditioning stimulus), and frequency facilitation (which occurs during low-frequency stimulation) were not inhibited. Calcium imaging confirmed that Cav2.3 channels contributed to R-type current and showed that calcium influx through R-type channels during individual action potentials was greater during high-frequency stimulation. These data identify a distinct role for presynaptic R-type channels at mossy fiber synapses and suggest a plausible mechanism that may contribute to certain forms of synaptic plasticity. Brenowitz and Regehr provide useful background information and discuss some of the implications of this research. D. Dietrich, T. Kirschstein, M. Kukley, A. Pereverzev, C. von der Brelie, T. Schneider, H. Beck, Functional specialization of presynaptic Cav2.3 Ca2+ channels. Neuron 39, 483-496 (2003).[Online Journal]S. D. Brenowitz, W. G. Regehr, "Resistant" channels reluctantly reveal their roles. Neuron 39, 391-394 (2003).[Online Journal]