Suppression of the voltage-gated K + current of human megakaryocytes by thrombin and prostacyclin

Abstract

We examined the effects of platelet activators and inhibitors of platelet function on the voltage-gated delayed rectifier K + current of human megakaryocytes. We found that both the activators such as thrombin, the thrombin receptor peptide (TRP 42–47) and ADP and the inhibitors such as prostacyclin suppressed the delayed rectifier current through two different mechanisms. The cAMP dependent protein kinase (A-kinase) inhibitor IP 20 blocked the suppression of the delayed rectifier current by prostacyclin and failed to block the suppression by thrombin, TRP 42–47 and ADP. The effects of IP 20 suggest that the action of prostacyclin is mediated by A-kinase and the action of the three activators is not mediated by A-kinase. Pertussis toxin (PTX) an inhibitor of the inhibitory GTP-binding proteins (G i) blocked the suppression of the delayed rectifier current by thrombin, TRP 42–47 and ADP and failed to block the suppression by prostacyclin. The effects of PTX suggests that the action of the three activators is mediated by G i or some other PTX-sensitive GTP-binding protein. We speculate that thrombin and other platelet activators that activate G i may be suppressing the delayed rectifier current via a direct interaction of G i or a subunit of it with the delayed rectifier potassium channel itself.