Plasma Membrane Ca²⁺ ATPases as Dynamic Regulators of Cellular Calcium Handling

Abstract

Plasma membrane Ca2+ ATPases (PMCAs) are essential components of the cellular toolkit to regulate and fine-tune cytosolic Ca2+ concentrations. Historically, the PMCAs have been assigned a housekeeping role in the maintenance of intracellular Ca2+ homeostasis. More recent work has revealed a perplexing multitude of PMCA isoforms and alternative splice variants, raising questions about their specific role in Ca2+ handling under conditions of varying Ca2+ loads. Studies on the kinetics of individual isoforms, combined with expression and localization studies suggest that PMCAs are optimized to function in Ca2+ regulation according to tissue- and cell-specific demands. Different PMCA isoforms help control slow, tonic Ca2+ signals in some cells and rapid, efficient Ca2+ extrusion in others. Localized Ca2+ handling requires targeting of the pumps to specialized cellular locales, such as the apical membrane of cochlear hair cells or the basolateral membrane of kidney epithelial cells. Recent studies suggest that alternatively spliced regions in the PMCAs are responsible for their unique targeting, membrane localization, and signaling cross-talk. The regulated deployment and retrieval of PMCAs from specific membranes provide a dynamic system for a cell to respond to changing needs of Ca2+ regulation.

Histone deacetylase inhibitor- and PMA-induced upregulation of PMCA4b enhances Ca2+ clearance from MCF-7 breast cancer cells

“…These pumps are responsible for the expulsion of increased intracellular Ca 2+ into the extracellular space [1,2]. The four major isoforms (PMCA1-4) are encoded by separate genes and, as a consequence of alternative RNA splicing, more than 20 variants exist.…”

“…The different PMCA variants show tissue-and cell-specific expression patterns and regulate in different ways the maintenance of the normally low cytosolic Ca 2+ concentration [3]. Therefore, the expression, localization and activity of the different PMCA isoforms need to be precisely controlled to fulfill properly their role [2,4].…”

“…PMCA4b is also known to interact with several signal and scaffold proteins which may connect this PMCA variant to specific signalling pathways [2]. As an example, the second intracellular loop of PMCA4b was shown to interact with the proapoptotic tumor supressor RASSF1 that may negatively regulate the EGF-induced ERK activation [67].…”

Modulation of Plasma Membrane Ca2+-ATPase by Neutral Phospholipids

“…They use the hydrolysis of ATP as a source of energy and share in common the formation of an acid-stable phosphorylated intermediate aspartyl-phosphate in their reaction cycle. The plasma membrane calcium pump (PMCA) 2 is a P-type ATPase that participates as an integral part of the Ca 2ϩ signaling mechanism from eukaryotic cells (1) and is thus a crucial component of cell function. The enzyme exists in two main conformations, E 1 and E 2 , according to the current kinetic model.…”

Alternative splice variants of plasma membrane calcium-ATPases in human corneal epithelium

“…The plasma membrane calcium ATPase (PMCA) is one of the enzymes responsible for maintaining low cytosolic calcium (Ca 2+ ) concentration through transmembrane transport of Ca 2+ against a large electrochemical gradient (Carafoli 1994;Strehler et al 2007). PMCA is a member of the P class of ion-motive ATPases forming an acylphosphate intermediate as part of its reaction mechanism (Dunham and Glynn 1961).…”