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: 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 (Cav3.2), but not [alpha]1G (Cav3.1) 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. [beta][gamma] reduces channel activity independent of voltage, a mechanism distinct from the established [beta][gamma]-dependent inhibition of non-L-type high-voltage-activated channels of the Cav2 family 6,7. These studies identify the [alpha]1H channel as a new effector for G-protein [beta][gamma] subunits, and highlight the selective signalling roles available for particular [beta][gamma] combinations.

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