Suppression of the voltage-gated K+ current of human megakaryocytes by thrombin and prostacyclin.
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 (TRP42-47) 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 IP20 blocked the suppression of the delayed rectifier current by prostacyclin and failed to block the suppression by thrombin, TRP42-47 and ADP. The effects of IP20 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 (Gi) blocked the suppression of the delayed rectifier current by thrombin, TRP42-47 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 Gi or some other PTX-sensitive GTP-binding protein. We speculate that thrombin and other platelet activators that activate Gi may be suppressing the delayed rectifier current via a direct interaction of Gi or a subunit of it with the delayed rectifier potassium channel itself.
Kapural
L
L
Department of Physiology, University of Connecticut Health Center, Farmington 06030, USA.
Fein
A
A
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000244:Adenosine Diphosphate / Q000494:pharmacology; D001853:Bone Marrow / Q000378:metabolism; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000494:pharmacology*; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects*; D008533:Megakaryocytes / Q000187:drug effects / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D010446:Peptide Fragments / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D015221:Potassium Channels / Q000378:metabolism*; D011450:Prostaglandin Endoperoxides, Synthetic / Q000494:pharmacology; D018179:Receptors, Thrombin / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology*; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D010446:Peptide Fragments; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D015221:Potassium Channels; D011450:Prostaglandin Endoperoxides, Synthetic; D018179:Receptors, Thrombin; C082835:thrombin receptor peptide (42-47); D005576:Colforsin; D004533:Egtazic Acid; D013928:Thromboxane A2; D000244:Adenosine Diphosphate; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C058824:IP 20; D011464:Epoprostenol; D000242:Cyclic AMP; D013917:Thrombin; D019204:GTP-Binding Proteins; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D015056:1-Methyl-3-isobutylxanthine