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

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Abstract
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 secretion1. 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 signals2,3,4,5, yet these signals have not been identified. Here we show that the inhibition of α1H (Cav3.2), but not α1G (Cav3.1) LVA Ca2+ channels is mediated selectively by β2γ2 subunits that bind to the intracellular loop connecting channel transmembrane domains II and III. This region of the α1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated α1G channels confers β2γ2-dependent inhibition. βγ reduces channel activity independent of voltage, a mechanism distinct from the established βγ-dependent inhibition of non-L-type high-voltage-activated channels of the Cav2 family6,7. These studies identify the α1H channel as a new effector for G-protein βγ subunits, and highlight the selective signalling roles available for particular βγ combinations.