The Plasma Membrane Calcium Pump: New Ways to Look at an Old Enzyme

Abstract

The three-dimensional structure of the PMCA pump has not been solved, but its basic mechanistic properties are known to repeat those of the other Ca 2؉ pumps. However, the pump also has unique properties. They concern essentially its numerous regulatory mechanisms, the most important of which is the autoinhibition by its C-terminal tail. Other regulatory mechanisms involve protein kinases and the phospholipids of the membrane in which the pump is embedded. Permanent activation of the pump, e.g. by calmodulin, is physiologically as harmful to cells as its absence. The concept is now emerging that the global control of cell Ca 2؉ may not be the main function of the pump; in some cell types, it could even be irrelevant. The main pump role would be the regulation of Ca 2؉ in cell microdomains in which the pump co-segregates with partners that modulate the Ca 2؉ message and transduce it to important cell functions.Decades of study on the mammalian Ca 2ϩ -ATPase of the plasma membrane (the PMCA pump) (1) have revealed many properties that set it apart from the other members of the superfamily of P-type pumps (2). One property that is immediately obvious is the long C-terminal tail, which is the locale of the numerous regulatory processes. Another distinctive property of the pump is the wealth of interactors with which the pump triggers processes of general significance for the cell. The basic information on these and other general aspects of the PMCA pump has been collected in other comprehensive reviews (3-5) and will not be repeated here. In this minireview, we instead look at the pump in a novel perspective, in which the extrusion of Ca 2ϩ will not be considered as a mechanism to regulate bulk cell Ca 2ϩ but will be integrated in a complex array of processes that modulate Ca 2ϩ -dependent processes within the cell (6). We focus on the most important regulatory mechanisms of the pump. We posit that, in many cell types, the quantitative contribution of the pump to the total extrusion of Ca 2ϩ could be minor or even irrelevant. Because the main role of the pump would be to do something else, the conclusion would offer a rationale for the puzzling finding that, in some plasma membranes, the pump coexists with a much more powerful Ca 2ϩ extrusion system, e.g. Na ϩ /Ca 2ϩ exchange in cardiomyocytes (7). Naturally, the function of the pump is still essential to the well being of the cell, as underscored by the causative involvement of its malfunction in disease processes (8).The pump contains 10 transmembrane domains, two main cytosolic loops, and a long cytosolic C-terminal tail (9, 10). Separate genes encode its four basic isoforms: PMCA1 is ubiquitous and has a housekeeping role; PMCA4 is also ubiquitous but is endowed with tissue-specific roles; and PMCA2 and PMCA3 are tissue-restricted, with high levels of expression in neurons. Complex alternative splicing processes at a site in the first cytosolic loop of the pump (site A) and within the C-terminal calmodulin-binding domain (CaM-BD 3 ; site C) generate numerous pum...

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