Selective regulation of N-type Ca channels by different combinations of G-protein β/γ subunits and RGS proteins

We examined the effects of G-protein β and γ subunit heterodimers on human α(1B) (N-type) Ca channels expressed in HEK293 cells. All of the known β subunits (β1-β5) produced voltage-dependent inhibition of α(1B) Ca channels, depending on the γ subunit found in the heterodimer. β1-β4 subunits inhibited Ca channels when paired with γ1-γ3. However, β5 subunits only produced inhibition when paired with γ2. In contrast, hererodimers between β5 subunits and RGS (regulators of G-protein signaling) proteins containing GGL domains did not produce inhibition of Ca channels. However, GGL domain-containing RGS proteins (e.g., RGS6 and RGS11) did block the ability of Gβ5/γ2 heterodimers to inhibit Ca channels. Because all of the G-protein β subunits are found in the nervous system, we conclude that they may all potentially participate in Ca channel inhibition. The interaction of GGL-containing RGS proteins with Gβ5γ2 suggests a novel way in which Ca channels can be regulated.