The molecular basis for T-type Ca2+ channel inhibition by G protein β2γ2 subunits

G ss gamma, a ubiquitous second messenger, relays external signals from G protein-coupled receptors to networks of intracellular effectors, including voltage-dependent calcium channels. Unlike high-voltage-activated Ca2+ channels, the inhibition of low-voltage-activated Ca2+ channels is subtype-dependent and mediated selectively by G ss(2)-containing dinners. Yet, the molecular basis for this exquisite selectivity remains unknown. Here, we used pure recombinant G ss gamma subunits to establish that the G ss(2)gamma(2) dinner can selectively reconstitute the inhibition of alpha(1H) channels in isolated membrane patches. This inhibition is the result of a reduction in channel open probability that is not accompanied by a change in channel expression or an alteration in active-channel gating. By exchanging residues between the active G ss(2) subunit and the inactive G ss(1) subunit, we identified a cluster of amino acids that functionally distinguish G ss(2) from other G ss subunits. These amino acids on the ss-torus identify a region that is distinct from those regions that contact the G alpha subunit or other effectors.