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 Calcium²+ -channel modulation involves activation of a heterotrimeric G protein to produce voltage-dependent inhibition [1]. Although it is widely assumed that G alpha mediates this effect, experiments to address this hypothesis directly are lacking. Here I show that transient overexpression of G beta gamma in sympathetic neurons mimics and occludes the voltage-dependent Calcium²+ channel modulation produced by noradrenaline (NA). Conversely, overexpression of G alpha produces minimal effects on basal Calcium²+ channel behaviour but attenuates NA-mediated inhibition 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 Calcium²+ channels. The identification of G beta gamma 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 Calcium²+ channels [2] and may modulate synaptic transmission by this mechanism [3,4].