The plasma membrane calcium pumps: focus on the role in (neuro)pathology

The plasma membrane Ca²⁺ ATPase (PMCA pump) is a member of the superfamily of P-type pumps. It is organized in the plasma membrane with ten transmembrane helices and two main cytosolic loops, one of which contains the catalytic center. It also contains a long C-terminal tail that houses the binding site for calmodulin, the main regulator of the activity of the pump. The pump also contains a number of other regulators, among them acidic phospholipids, kinases, and numerous protein interactors. Separate genes code for 4 basic pump isoforms in mammals, additional isoform complexity being generated by the alternative splicing of primary transcripts. Pumps 1 and 4 are expressed ubiquitously, pumps 2 and 3 are tissue restricted, with preference for the nervous system. In essentially all cells, the pump coexists with much more powerful systems that clear Ca²⁺ from the cytosol, e.g. the SERCA pump and the Na⁺/Ca²⁺ exchanger. Its role in the global regulation of cellular Ca²⁺ homeostasis is thus quantitatively marginal: its main function is the regulation of Ca²⁺ signaling in selected sub-plasma membrane microdomains where Ca²⁺ modulated interactors also reside. Malfunctions of the pump linked to genetic mutations are now described with increasing frequency, the disease phenotypes being especially severe in the nervous system where isoforms 2 and 3 predominate. The analysis of the pump defects suggests that the disease phenotypes are likely to be related to the imperfect modulation of Ca²⁺ signaling in selected sub-plasma membrane microdomains, leading to the defective control of the activity of important Ca²⁺ dependent interactors.