Alpha-adrenergic inhibition of sympathetic neurotransmitter release mediated by modulation of N-type calcium-channel gating.
In sympathetic neurons, catecholamines interact with prejunctional alpha-adrenergic receptors to reduce delivery of transmitter to postjunctional target organs. This autoinhibitory feedback is a general phenomenon seen in diverse neurons containing a variety of transmitters. The underlying mechanisms of alpha-adrenergic inhibition are not clear, although decreases in cyclic AMP and cAMP-mediated phosphorylation have been implicated. We have studied depolarization-induced catecholamine release and calcium-channel currents in frog sympathetic neurons. Here we show that alpha-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 release, 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 alpha-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.
Lipscombe
D
D
Department of Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510.
Kongsamut
S
S
Tsien
R W
RW
D000818:Animals; D003994:Bucladesine / Q000494:pharmacology; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology; D005728:Ganglia, Sympathetic / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D006160:Guanosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D066298:In Vitro Techniques; D008564:Membrane Potentials; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D011898:Ranidae; D011942:Receptors, Adrenergic, alpha / Q000502:physiology*; D012636:Secretory Rate / Q000187:drug effects; D013873:Thionucleotides / Q000494:pharmacology
D015220:Calcium Channels; D018377:Neurotransmitter Agents; D011942:Receptors, Adrenergic, alpha; D013873:Thionucleotides; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D003994:Bucladesine; D006160:Guanosine Triphosphate; D019204:GTP-Binding Proteins; D002118:Calcium; D009638:Norepinephrine