VOLTAGE-DEPENDENT MODULATION OF N-TYPE CALCIUM CHANNELS BY G-PROTEIN BETA-GAMMA-SUBUNITS

THE most commonly used signal transduction pathway for receptor-mediat ed N-type Ca2+-channel modulation involves activation of a heterotrime ric G protein to produce voltage-dependent inhibition(1). Although it is widely assumed that G alpha mediates this effect, experiments to ad dress this hypothesis directly are lacking. Here I show that transient overexpression of G beta gamma in sympathetic neurons mimics and occl udes the voltage-dependent Ca2+ channel modulation produced by noradre naline (NA). Conversely, overexpression of G alpha produces minimal ef fects on basal Ca2+ channel behaviour but attenuates NA-mediated inhib ition in a manner consistent with the buffering of G beta gamma. These observations indicate that it is G beta gamma, and not G alpha, that mediates voltage-dependent inhibition of N-type Ca2+ channels. The ide ntification of G beta gamma as the mediator of this pathway has broad implications as G-protein-coupled receptors, many of which are implica ted in disease or are targets of therapeutic agents, couple to N-type Ca2+ channels(2) and may modulate synaptic transmission by this mechan ism(3,4).