title: The plasma membrane calcium pumps: focus on the role in (neuro)pathology.
abstract: 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.
authors.affiliation: Dept. of Biology, University of Padova, 35131 Padova, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Brini
authors.affiliation: Venetian Institute of Molecular Medicine, 35129 Padova, Italy.
authors.forename: Ernesto
authors.initials: E
authors.lastname: Carafoli
authors.affiliation: Dept. of Biomedical Sciences, University of Padova, 35131 Padova, Italy. Electronic address: tito.cali@unipd.it.
authors.forename: Tito
authors.initials: T
authors.lastname: Calì
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D006801:Humans; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D053499:Plasma Membrane Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*
chemical_list: D053499:Plasma Membrane Calcium-Transporting ATPases
keywords: Cerebellar ataxia; Genetic deafness; PMCA mutations; Plasma membrane Ca(2+) pumps; Pump isoforms; Spastic paraplegia