Receptor-Mediated Modulation of Voltage-Dependent Ca²⁺ Channels via Heterotrimeric G-proteins in Neurons

Abstract

The activity of voltage-dependent Ca²⁺ channels is highly regulated by neurotransmitter receptors coupled to heterotrimeric G-proteins. In the expression studies using cloned Ca²⁺ channel subunits, it has been clarified that the main mechanism of the inhibition of N-type channel current is mediated directly by G-protein βγ subunits in a membrane-delimited and voltage-sensitive manner. In addition, recent studies have also clarified that N-type channels are modulated by several G-protein α subunits in different ways. Among them, G_αo mediates a voltage-resistant inhibition of N-type current by neurotransmitters. This type of inhibition is more apparent in the case of P/Q-type channels in both native cells and expression systems. Moreover, other G-protein subunits, such as G_αq and G_αs, also seem to regulate N-type channels in a membrane-delimited manner. The fine tunings of Ca²⁺ channel activity by intracellular proteins have physiological and pathological meanings in the regulation of Ca²⁺ influx into excitable cells by neurotransmitters and pharmacological implications as novel drug targets for controlling Ca²⁺ influx.