Modulation of Calcium sup 2+ channels by G-protein beta gamma subunits

CALCIUM ions entering cells through voltage-gated Calcium²+ channels initiate rapid release of neurotransmitters and secretion of hormones. Calcium²+ currents can be inhibited in many cell types by neurotransmitters acting through G proteins via a membrane-delimited pathway independently of soluble intracellular messengers [1-4]. Inhibition is typically caused by a positive shift in the voltage dependence and a slowing of channel activation and is relieved by strong depolarization resulting in facilitation of Calcium²+ currents [1,4-6]. This pathway regulates the activity of N-type and P/Q-type Calcium sup 2+ channels [1,2,7], which are localized in presynaptic terminals [8,9] and participate in neurotransmitter release [10-13]. Synaptic transmission is inhibited by neurotransmitters through this mechanism [1,4]. G-protein alpha subunits confer specificity in receptor coupling [1-4,14-17], but it is not known whether the G alpha or G beta gamma subunits are responsible for modulation of Calcium²+ channels. Here we report that G beta gamma subunits can modulate Calcium²+ channels. Transfection of G beta gamma into cells expressing P/Q-type Calcium²+ channels induces modulation like that caused by activation of G protein-coupled receptors, but G alpha subunits do not. Similarly, injection or expression of G beta gamma subunits in sympathetic ganglion neurons induces facilitation and occludes modulation of N-type channels by noradrenaline, but G alpha subunits do not. In both cases, the G gamma subunit is ineffective by itself, but overexpression of exogenous G beta subunits is sufficient to cause channel modulation.