The molecular basis for T-type Ca 2+ channel inhibition by G protein β 2 γ 2 subunits

Gβγ, 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 Ca 2+ channels, the inhibition of low-voltage-activated Ca 2+ channels is subtype-dependent and mediated selectively by Gβ 2 -containing dimers. Yet, the molecular basis for this exquisite selectivity remains unknown. Here, we used pure recombinant Gβγ subunits to establish that the Gβ 2 γ 2 dimer can selectively reconstitute the inhibition of α 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 Gβ 2 subunit and the inactive Gβ 1 subunit, we identified a cluster of amino acids that functionally distinguish Gβ 2 from other Gβ subunits. These amino acids on the β-torus identify a region that is distinct from those regions that contact the Gα subunit or other effectors.