Mode of regulation by G protein of the ATP‐sensitive K+ channel in guinea‐pig ventricular cell membrane.

1. The effect of G protein activation on the ATP‐sensitive K+ (K+ATP) channel was examined in inside‐out patches from guinea‐pig ventricular myocytes. At low (0.3 mM) intracellular ATP concentration ([ATP]i) in the bathing solution, in the absence of agonists in the pipette, guanosine 5'‐O‐(3‐thiotriphosphate) (GTP gamma S) or AlF4‐ applied to the intracellular side of the patch membrane gradually activated the K+ATP channel. The activation by GTP gamma S was irreversible, although high [ATP]i could completely close the channel. 2. In ATP‐free media GTP gamma S did not increase further the activity of the fully active channel, and was unable to reactivate the channel in the non‐operative state after rundown. [ATP]i‐channel activity curves constructed before and after GTP gamma S application demonstrated that GTP gamma S shifts the half‐inhibitory [ATP]i from 19.5 to 110 microM without changing the Hill coefficient. 3. When acetylcholine or adenosine was included in the pipette, intracellular GTP reversibly activated the K+ATP channel which was partially inhibited by [ATP]i. 4. These results indicate that G protein may stimulate myocardial K+ATP channels in the operative state by reducing the potency of ATP inhibition. The possible coupling of the G protein with muscarinic as well as A1 adenosine receptors is suggested.