The molecular basis for T-type Ca2+ channel inhibition by G protein β2γ2 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 Ca²⁺ channels, the inhibition of low-voltage-activated Ca²⁺ channels is subtype-dependent and mediated selectively by Gβ₂-containing dimers. Yet, the molecular basis for this exquisite selectivity remains unknown. Here, we used pure recombinant Gβγ subunits to establish that the Gβ₂γ₂ 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 Gβ₂ subunit and the inactive Gβ₁ subunit, we identified a cluster of amino acids that functionally distinguish Gβ₂ 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.