Phenothiazine inhibition of calmodulin stimulates calcium-dependent potassium efflux in human red blood cells.
Elevation of red blood cell calcium increases the efflux of potassium. The active extrusion of calcium from the red cell is regulated by calmodulin. Phenothiazines bind to calmodulin in a calcium-dependent manner preventing the calmodulin from activating a wide variety of cellular processes. The present study shows that phenothiazines increase the efflux of potassium from red cells incubated with the calcium ionophore A23187. The dose dependent effect of trifluoperazine on potassium efflux correlates with its inhibition of Ca-ATPase activity. The phenothiazine effects are dependent upon ATP in that increases in potassium efflux are not observed in energy depleted cells. In calcium buffered ghosts no direct effect of calmodulin or an antibody to calmodulin can be shown. These data suggest that phenothiazines stimulate calcium-dependent potassium loss indirectly by a drug-induced blockage of the calmodulin-activated Ca-ATPase.
D000255:Adenosine Triphosphate / Q000097:blood; D001693:Biological Transport, Active / Q000187:drug effects; D000001:Calcimycin / Q000494:pharmacology; D002118:Calcium / Q000097:blood / Q000494:pharmacology*; D000252:Calcium-Transporting ATPases / Q000037:antagonists & inhibitors; D002147:Calmodulin / Q000037:antagonists & inhibitors*; D002746:Chlorpromazine / Q000494:pharmacology; D004912:Erythrocytes / Q000378:metabolism*; D005476:Fluphenazine / Q000494:pharmacology; D006801:Humans; D010640:Phenothiazines / Q000494:pharmacology*; D011188:Potassium / Q000097:blood*; D014268:Trifluoperazine / Q000494:pharmacology
D002147:Calmodulin; D010640:Phenothiazines; D014268:Trifluoperazine; D000001:Calcimycin; D000255:Adenosine Triphosphate; D000252:Calcium-Transporting ATPases; D011188:Potassium; D005476:Fluphenazine; D002118:Calcium; D002746:Chlorpromazine