Structure, Function and Regulation of the Plasma Membrane Calcium Pump in Health and Disease

Abstract

In this review, I summarize the present knowledge of the structural and functional properties of the mammalian plasma membrane calcium pump (PMCA). It is outlined how the cellular expression of the different spliced isoforms of the four genes are regulated under normal and pathological conditions.

The PLEKHA7–PDZD11 complex regulates the localization of the calcium pump PMCA and calcium handling in cultured cells

“…PMCA1 and PMCA2 b-isoforms, but not PMCA4, interact with the Na + /H + exchanger regulatory factor (NHERF2), which enhances their surface concentration and membrane retention by tethering the pump to the underlying actin cytoskeleton ( 47 , 48 , 49 , 50 ). The PBM of PMCA b-isoforms can mediate PMCA dimerization, leading to increased activity ( 51 , 52 ) and facilitate the recruitment of scaffolding and signaling complexes, suggesting specialized signaling roles for different PMCA isoforms ( 17 , 19 ). For example, subcompartmentalized Ca 2+ microdomains generated by PMCA isoforms represent an ideal microenvironment for the regulation of their downstream signaling, as shown for nitric oxide synthase-1 (NOS-1) ( 53 , 54 ).…”

“…The plasma membrane calcium ATPase (PMCA) is an essential transmembrane pump, which controls cellular calcium levels by extruding Ca 2+ from the cytoplasm toward the extracellular space ( 15 ). The localization of PMCA isoforms to distinct membrane domains and microdomains is important for cellular signaling ( 16 , 17 , 18 , 19 ). In mammals, four genes encode PMCA isoforms 1 to 4, with additional isoform diversity generated by alternative mRNA splicing ( 20 , 21 ).…”

Plasma membrane Ca2+ pump isoform 4 function in cell migration and cancer metastasis

“…Additional proteins such as the tumour suppressor Ras‐associated factor 1A (RASSF1A), the Ca 2+ ‐dependent phosphatase calcineurin, the endothelial nitric oxide synthase (eNOS) and the trafficking protein 14‐3‐3 Ɛ have been shown to interact with specific regions of the catalytic core, and the last with the N‐terminal tail of PMCAs in an isoform‐specific manner. More information on the interaction of the PMCA isoforms can be found in recent reviews (Krebs, 2022; Padányi et al., 2016; Stafford et al., 2017; Strehler, 2015), and details regarding the PMCA4b variant are described in ‘Regulation of PMCA4 expression and activity’ below.…”

Ca2+ Homeostasis by Plasma Membrane Ca2+ ATPase (PMCA) 1 Is Essential for the Development of DP Thymocytes

“…PMCA2 and 3 are mainly expressed in excitable cells such as neurons and inner ear hair cells [ 22 , 23 , 24 , 25 ], and mutations in PMCA2 and 3, thus, can cause deafness or ataxia in mice and humans [ 26 , 27 , 28 , 29 ]. PMCA1 and 4 are ubiquitously expressed, particularly in non-excitable cells such as immune cells [ 30 ]. PMCAs are mainly activated by Ca 2+ /Calmodulin besides other mechanisms and their function and stability is dependent on the interaction with Neuroplastin and/or Basigin [ 31 , 32 , 33 , 34 ].…”

“…PMCA1 and PMCA4 are the only isoforms expressed in T cells and both are upregulated in stimulated T cells [ 33 , 40 , 41 ]. Several studies in Jurkat T cells and primary human T cells have shown that PMCA4 tunes TCR-induced SOCE within certain microdomains of the T cell immune synapse [ 30 , 40 , 42 , 43 , 44 , 45 ]. There, it acts both as a negative or as a positive regulator of SOCE and NFAT activation depending on its exact positioning.…”