α-Adrenergic inhibition of sympathetic neurotransmitter release mediated by modulation of N-type calcium-channel gating

Abstract

IN sympathetic neurons, catecholamines interact with prejunctional α-adrenergic receptors to reduce delivery of transmitter to postjunctional target organs1-4. This autoinhibitory feedback is a general phenomenon seen in diverse neurons containing a variety of transmitters2-4. The underlying mechanisms of α-adrenergic inhibition are not clear, although decreases in cyclic AMP and cAMP-mediated phosphorylation have been implicated1-4 (compare ref. 5). We have studied depolarization-induced catecholamine release and calcium-channel currents in frog sympathetic neurons. Here we show that α-adrenergic inhibition of transmitter release can be explained by inhibition of Ca2+-channel currents and not by modulation of intracellular proteins. Noradrenaline strongly reduces the activity of N-type Ca2+ channels, the dominant calcium entry pathway triggering sympathetic transmitter release6, whereas L-type Ca2+ channels are not significantly inhibited. The down-modulation of N-type channels involves changes in rapid gating kinetics but not in unitary flux. This is the first detailed description of inhibition of a high-voltage activated neuronal Ca2+ channel at the single-channel level. The coupling between α-adrenergic receptors and N-type channels involves a G protein, but not a readily diffusible cytoplasmic messenger or protein kinase C, and may be well suited for rapid and spatially localized feedback-control of transmitter release.

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