ras p21 and GAP inhibit coupling of muscarinic receptors to atrial K+ channels

Abstract

The signal-transducing G protein Gk couples muscarinic receptors to K+ (K+[ACh]) channels in atrial cells. Recombinant human ras p21 GAP (GTPase activating protein) at subnanomolar concentrations inhibited GTP-dependent channel opening in isolated atrial cell membranes. This inhibition depended on interaction of GAP with ras p21 in the isolated membranes. In addition, recombinant ras p21 proteins blocked the currents; this effect could be blocked by prior incubation of membranes with specific anti-GAP antibodies. We therefore propose that ras p21 GTP complexed with GAP (ras p21-GAP) blocks K+[ACh] currents. The channel block could be overcome by GTP gamma S activation of endogenous Gk; this indicates that ras p21-GAP does not interfere with interaction of Gk with the K+[ACh] channel directly, but prevents coupling of the muscarinic receptor to endogenous Gk.