A new form of phospholipase A2 (PLA2) associated with the cytoskeleton of human red cells inhibits Na,K-ATPase at the concentrations of intracellular free calcium that occur during cell activation. This form of PLA2 may also be present in neurons, where it could mediate the effects of intracellular calcium on Na,K-ATPase. Regulation of Na,K-ATPase in neurons by calcium has been linked to the control of neurotransmitter release and has been implicated in the development of bipolar disorders. The data in red cells suggest a single PLA2 that exists in two forms: phosphorylated and unphosphorylated. When phosphorylated, PLA2 is activated by micromolar (0.2-10 uM) free calcium by the binding of calmodulin (CaM). In the absence of phosphorylation, PLA2 is directly activated my millimolar (0.1-1 mM) calcium. This membrane-associated PLA2 has properties distinct from other PLA2s based on its activation by CaM, its sensitivity to both micromolar and millimolar calcium, and its response to inhibitors.
The specific aims are to determine (1) the molecular basis for the Ca/CaM stimulated PLA2 and (2) how the Ca/CaM PLA2 affects the Na,K-ATPase. The results will define a new Ca/CaM-PLA2 capable of participating in cell signaling and of regulating Na,K-ATPase in response to changes intracellular free calcium. The studies will be carried out in red cells due to their advantages as a simple model system, but should be applicable to other cells, including neurons, where Na,K-ATPase is also inhibited by changes in intracellular free calcium.
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