Apart from its known function, the plasma membrane Ca2+atpase can regulate Ca2+ signaling by controlling phosphatidylinositol 4,5-bisphosphate levels

Plasma membrane Ca 2+ ATPases (PMCAs) are known targets of phosphatidylinositol-4,5-bisphosphate (PIP 2 ), but if and how they control the PIP 2 pool has not been considered. We demonstrate here that PMCAs protect PIP 2 in the plasma membrane. Comparison of active and inactive PMCAs indicates that the protection operates by 2 mechanisms; one requiring active PMCA, the other not. It appears that the mechanism requiring activity is the removal of the Ca 2+ required for sustained phospholipase C (PLC) activity, while the mechanism not requiring activity is PIP 2 binding. We show that in PMCA overexpressing cells, PIP 2 binding can lead to less IP 3 and diminished Ca 2+ release from intracellular Ca 2+ pools. Inspection of a homology model of PMCA suggests that PMCAs have a conserved cluster of basic residues forming a “blue collar” at the interface between the membrane core and the cytoplasmic domains. By molecular dynamics simulation we found that the blue collar forms four binding pockets for the phosphorylated inositol head group of PIP 2 ; these pockets bound PIP 2 strongly and frequently. Our studies suggest that by having the ability to bind PIP 2 , PMCAs can control the accessibility of PIP 2 for PLC and other PIP 2 mediated processes.