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.

FIGURE 1

Scheme of the PMCA. The membrane-spanning regions are numbered and shown as shaded boxes. The amino- (N) and carboxyl-terminal (C) ends are labeled, P denotes the obligatory aspartyl-phosphate formed during the reaction cycle, and ATP indicates the region involved in nucleotide (ATP) binding. The phospholipid-sensitive region (PL), the calmodulin-binding region and the PDZ-binding motif at the C-terminus of all PMCA b-splice variants are shown as gray boxes. The PMCA is represented in its activated state with Ca²⁺-calmodulin (Ca²⁺-CaM) bound to the C-tail. Arrows labeled “splice site A” and “splice site C” denote the regions affected by alternative splicing. A hatched box indicates the peptide segment encoded by alternatively spliced exon(s) at site A; at site C the two major splice variants (“a” and “b”) are shown as separate tails to indicate their divergent reading frames.

FIGURE 2

PMCA-interacting proteins and their possible roles in pump regulation and function. PMCA-interacting proteins are listed near the domain of the PMCA to which they bind. Suspected or known functional roles of these different protein interactions are indicated in italics. Note that no binding partners (sorting proteins?) have yet been identified for the fist cytosolic loop of the PMCA carrying the A-splice. Also note that except for calmodulin (CaM), all proteins listed as binding to the C-terminal tail of the PMCA are specific for the b-splice variants and do not interact with the a-splice variants. For details, see the text.