T-type calcium channel regulation by specific G-protein βγ subunits

Low-voltage-activated (LVA) T-type calcium channels have a wide tissue distribution and have well-documented roles in the control of action potential burst generation and hormone secretion(1). In neurons of the central nervous system and secretory cells of the adrenal and pituitary, LVA channels are inhibited by activation of G-protein-coupled receptors that generate membrane-delimited signals(2-5), yet these signals have not been identified. Here we show that the inhibition of alpha(1H) (Ca(v)3.2), but not alpha(1G) (Ca(v)3.1) LVA Ca2+ channels is mediated selectively by beta(2)gamma(2) subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the alpha(1H) channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated alpha(1G) channels confers beta(2)gamma(2)-dependent inhibition. betagamma reduces channel activity independent of voltage, a mechanism distinct from the established betagamma-dependent inhibition of non-L-type high-voltage-activated channels of the Ca(v)2 family(6,7). These studies identify the alpha(1H) channel as a new effector for G-protein betagamma subunits, and highlight the selective signalling roles available for particular betagamma combinations.