Effects of PKCalpha activation on Ca2+ pump and KCa channel in deoxygenated sickle cells |
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Authors: | Fathallah, Hassana Sauvage, Monique Romero, Jose R. Canessa, Mitzy Giraud, Francoise |
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Abstract: | We have previously shown that a pretreatment with phorbol12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC),reduced deoxygenation-induced K+loss and Ca2+ uptake and preventedcell dehydration in sickle anemia red blood cells (SS cells) (H. Fathallah, E. Coezy, R.-S. De Neef, M.-D. Hardy-Dessources, and F. Giraud. Blood 86: 1999-2007,1995). The present study explores the detailed mechanism of thisPMA-induced inhibition. The main findings are, first, the detection ofPKC and PKC in normal red blood cells and the demonstration that both isoforms are expressed at higher levels in SS cells. The -isoform only is translocated to the membrane and activated by PMAand by elevation of cytosolicCa2+. Second, PMA is demonstratedto activate Ca2+ efflux indeoxygenated SS cells by a direct stimulation of the Ca2+ pump. PMA, moreover, inhibitsdeoxygenation-induced, charybdotoxin-sensitive K+ efflux in SS cells. Thisinhibition is partly indirect and explained by the reduceddeoxygenation-induced rise in cytosolicCa2+ resulting fromCa2+ pump stimulation. However, asignificant inhibition of theCa2+-activatedK+ channels(KCa channels) by PMA can also bedemonstrated when the channels are activated byCa2+ plus ionophore, underconditions in which the Ca2+ pumpis operating near its maximal extrusion rate, but swamped byCa2+ plus ionophore. The data thussuggest a PKC-mediated phosphorylation both of theCa2+ pump and of theKCa channel or an auxiliaryprotein. |
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