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. 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^,,,, yet these signals have not been identified. Here we show that the inhibition of α_1H (Ca_v3.2), but not α_1G (Ca_v3.1) 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 α_1H channel is crucial for inhibition, because its replacement abrogates inhibition and its transfer to non-modulated α_1G 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 Ca_v2 family^,. These studies identify the α_1H channel as a new effector for G-protein βγ subunits, and highlight the selective signalling roles available for particular βγ combinations.