Several neurotransmitters and hormones acting through G protein-coupled receptors elicit a voltage-dependent regulation of Ca(v)2.2 channels, having profound effects on cell function and the organism. It has been hypothesized that protein-protein interactions define specificity in signal transduction. Yet it is unknown how the molecular interactions in an intracellular signaling cascade determine the specificity of the voltage-dependent regulation induced by a specific neurotransmitter. It has been suspected that specific effector regions on the G beta subunits of the G proteins are responsible for voltage-dependent regulation. The present study examines whether a neurotransmitter's specificity can be revealed by simple ion-current kinetic analysis likely resulting from interactions between G beta subunits and the channel-molecule. Noradrenaline is a neurotransmitter that induces voltage-dependent regulation. By using biochemical and patch-clamp methods in rat sympathetic neurons we examined calcium current modulation induced by each of the five G beta subunits and found that G beta(2) mimics activation kinetic slowing of Ca(v)2.2 channels by noradrenaline. Furthermore, overexpression of the G beta(2) isoform reproduces the effect of noradrenaline in the willing-reluctant model. These results advance our understanding on the mechanisms by which signals conveying from a variety of membrane receptors are able to display precise homeostatic responses. (C) 2014 Elsevier Inc. All rights reserved.