ATP-sensitive K+ (K+[ATP]) current is thought to be regulated by GTP-binding proteins (G proteins), but the pathways that couple receptor, G protein, and channel have not been defined. We studied regulation of tolbutamide-sensitive K+[ATP] current in neonatal rat ventricular myocytes. Application of 0.1 mM ATP to the intracellular side of membrane patches reduced K+ [ATP] channel activity, and addition of the nonhydrolyzable GTP analogue guanosine 5'-O-(3-thiotriphosphate) (GTP gamma S) at 0.1 mM restored activity. Application of 0.1 mM intracellular GTP plus 10 microM extracellular adenosine or 100 nM N6-cyclohexyladenosine had the same effect as GTP gamma S; hence K+[ATP] channels may be coupled to adenosine receptors via G proteins. To determine which G protein, we applied G alpha subunits, preactivated with GTP gamma S to the cytoplasmic side of membrane patches, and found that alpha i1, alpha i2, and alpha i3 mimicked the effect of GTP gamma S, but not alpha o or Gs, suggesting that Gi alpha acts via a membrane-delimited pathway. Adenosine receptor coupling may be important for activating K+[ATP] channels in ischemic muscle.
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