Voltage-dependent modulation of N-type calcium channels by G-protein beta gamma subunits.
The most commonly used signal transduction pathway for receptor-mediated N-type Ca2+-channel modulation involves activation of a heterotrimeric G protein to produce voltage-dependent inhibition. Although it is widely assumed that Galpha mediates this effect, experiments to address this hypothesis directly are lacking. Here I show that transient overexpression of Gbetagamma in sympathetic neurons mimics and occludes the voltage-dependent Ca2+ channel modulation produced by noradrenaline (NA). Conversely, over-expression of Galpha produces minimal effects on basal Ca2+ channel behaviour but attenuates NA-mediated inhibition in a manner consistent with the buffering of Gbetagamma. These observations indicate that it is Gbetagamma, and Galpha, that mediates voltage-dependent inhibition of N-type Ca2+ channels. The identification of Gbetagamma as the mediator of this pathway has broad implications as G-protein-coupled receptors, many of which are implicated in disease or are targets of therapeutic agents, couple to N-type Ca2+ channels and may modulate synaptic transmission by this mechanism.
Ikeda
S R
SR
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912-2300, USA.
D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D002417:Cattle; D046508:Culture Techniques; D018076:DNA, Complementary; D004563:Electrochemistry; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism*; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism
D015220:Calcium Channels; D018076:DNA, Complementary; D006165:Guanylyl Imidodiphosphate; D019204:GTP-Binding Proteins; D009638:Norepinephrine