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 mu M 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 A(1) adenosine receptors is suggested.