Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Plasma Membrane Calcium-Transporting ATPase

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_133

Synonyms

Historical Background

The existence of a plasma membrane calcium-transporting ATPase (PMCA) that actively pumps Ca2+ ions out of the cell was first demonstrated in erythrocyte (red blood cell) membranes by Schatzmann (1966). Because of its generally low abundance and difficult biochemical properties, it took over a decade until the PMCA was first isolated in purified form. Crucial for the successful purification was the discovery that the PMCA binds with high affinity, and in a Ca2+-dependent manner, to the Ca2+ sensor protein calmodulin (Niggli et al. 1979). Subsequent work showed that at least one type of plasma membrane Ca2+ ATPase is found in all eukaryotic cells including those from fungi, animals, and plants (Axelsen and Palmgren 1998; Thever and Saier 2009). It is now well established that active Ca2+ expulsion by the PMCAs is an essential component of eukaryotic cellular Ca2+ handling. Although, PMCAs were originally thought to be required mainly for the “housekeeping” function of maintaining and resetting the low intracellular free [Ca2+] levels, recent studies have shown that these pumps are also active participants in global and local Ca2+ signaling (Strehler 2016).

General Structure and Isoforms

PMCAs belong to the large superfamily of P-type ion-transporting ATPases, where they are classified as IIB subfamily (Axelsen and Palmgren 1998) or family 2 in the IUBMB transporter classification system (Thever and Saier 2009; see www.tcdb.org). The characteristic feature of P-type ATPases is the formation of an obligatory phosphorylated intermediate during the reaction cycle (Pedersen and Carafoli 1987). The PMCA consists of a single polypeptide, which in vertebrates contains about 1200 amino acids and has a molecular mass of about 140 kDa. The protein has 10 membrane-spanning segments, and both the N- and the C-terminal ends are facing the cytosol. Most of the protein mass is on the cytosolic side of the membrane, only short loops connecting pairs of transmembrane segments are facing the extracellular side. Figure 1 schematically illustrates the domain arrangement of the PMCA in a 2-dimensional model.
Plasma Membrane Calcium-Transporting ATPase, Fig. 1

Scheme of the plasma membrane Ca2+-transporting ATPase, showing major domains and sites affected by alternative splicing. The 10 membrane-spanning regions are numbered and shown as cylinders forming the M domain. The amino- (N-term) and carboxy-terminal ends (C-term), the conserved aspartate (Asp) residue undergoing phosphorylation during the reaction cycle, and the ATP binding site (ATP) are labeled. The direction of Ca2+ transport is indicated by an arrow. The three main cytosolic domains are labeled A (actuator), P (phosphorylation), and N (nucleotide-binding). Splice sites A and C are indicated by arrows. Splicing at site C affects the calmodulin-binding (CaM-bdg) domain and results in major splice variants “a” and “b,” which differ in their C-terminal amino acid sequence. The “b” splice variants contain a C-terminal PDZ-binding motif, which is missing in the “a” variants

The cytosolic loops between transmembrane segments 2 and 3 and between transmembrane segments 4 and 5 are large and contribute the bulk of the mass to the so-called A (actuator) and N/P (nucleotide-binding/catalytic phosphorylation) domains, respectively. In animal PMCAs, the C-terminal tail following the last membrane-spanning segment is about 150 residues long and contains the auto-inhibitory regulatory sequences and the high-affinity calmodulin-binding domain. In contrast, in several plant PMCAs, the calmodulin-binding and auto-inhibitory regulatory domain are instead found in the extended N-terminal tail. The three-dimensional structure of the PMCA has not yet been solved in atomic detail, but based on the high conservation of secondary structure elements (including the 10 transmembrane helices and the functionally important A, N, and P domains), the general structure of the PMCA is thought to be very similar to that of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA), for which several high-resolution x-ray structures are available (Toyoshima 2009; Moeller et al. 2010).

Mammalian PMCAs are encoded by four separate genes, which give rise to PMCA isoforms 1–4. The human genes (gene symbols ATP2B1-ATP2B4) are located on chromosomes 12q21.3, 3p25.3, Xq28, and 1q32.1, respectively, whereas the orthologous mouse genes (Atp2b1-Atp2b4) are on chromosomes 10C3, 6E3, XA7.3, and 1E4. The RNA transcripts of all genes are subject to complex alternative splicing, resulting in over 30 possible PMCA splice variants. The two major sites (sites A and C) where alternative splicing affects the PMCA protein structure are indicated in Fig. 1. Figure 2 shows a scheme of the resulting splice variants identified in human PMCAs. The two major splice variants generated at site C are “a” and “b”; they differ significantly in their C-terminal tails because of a change in the open reading frame introduced by the splice. In contrast, splice variants generated at site A (“w,” “x,” “z”) contain different peptide insertions in the first cytosolic loop, but otherwise retain the same reading frame. Alternative splicing affects the cellular targeting and the regulatory and functional properties of the different PMCA isoforms, and thus plays an essential role in the dynamic regulation of Ca2+ signaling in cell physiology (Strehler and Zacharias 2001).
Plasma Membrane Calcium-Transporting ATPase, Fig. 2

Alternative splicing options of human PMCA isoforms 1–4 at splice sites A and C. The exon structure of the region involved in alternative splicing is shown for each of the four human PMCA (ATP2B) genes. Constitutively spliced exons are shown as gray boxes. The sizes of alternatively spliced exons (different shades of gray) are given in nucleotides, the splice options are indicated by connecting lines, and the resulting splice products are labeled by their lowercase symbol. Note that in PMCA1, only splice option “x” has been detected at site A; and that in PMCA3 and PMCA4, splice variant “e” results from a read-through of the last alternatively spliced exon into the adjoining intron (indicated as thin white box)

Regulation and Functional Properties

The basic function of the PMCA is to catalyze the “uphill” transport of Ca2+ ions across the membrane. PMCAs couple the hydrolysis of one molecule of ATP to the transport of 1 Ca2+ ion across the membrane. They are high-affinity, but low capacity, Ca2+ transporters with a maximal turnover number of ∼100/s (Brini and Carafoli 2009). Their general reaction mechanism is conveniently described by the E1–E2 scheme (Fig. 3), in which the pump toggles between two major conformational states E1 and E2. Thus, transport of a Ca2+ ion from the intracellular (cytosolic) side to the extracellular side of the membrane is accompanied by large conformational changes in the PMCA. These are a result of the reactions taking place at the intracellular ATP binding and phosphorylation site (where the γ-phosphate of ATP is transferred to an invariant Asp residue), which are coupled to rearrangement of the membrane-spanning domain of the PMCA. The positive charge transfer resulting from the transport of Ca2+ across the membrane is at least partially compensated by countertransport of protons (H+). Accordingly, the PMCA is sensitive to pH, with alkaline pH in the extracellular milieu having an inhibitory effect.
Plasma Membrane Calcium-Transporting ATPase, Fig. 3

Reaction scheme for the plasma membrane Ca2+−transporting ATPase. The PMCA assumes two major states E1 and E2. E1 has high affinity for Ca2+ on the cytosolic side (Ca2+ cyt). Ca2+ binding stimulates the ATPase activity of the pump, resulting in the phosphorylation of a conserved Asp residue and formation of the phosphorylated intermediate (E1∼P), as well as occlusion (occ) of the bound transport Ca2+ ion. The Ca2+ ion is translocated across the membrane, and the stored energy is released during the conformational transition from the E1∼P to the E2–P state. The Ca2+ affinity of the E2–P state is low and Ca2+ dissociates on the extracellular side of the membrane (Ca2+ ex). Hydrolysis of the phosphoenzyme E2–P and conformational rearrangement of the E2 to the E1 state complete the cycle. The positive charge movement during Ca2+ transport is at least partially compensated by countertransport of protons (H+)

At low intracellular [Ca2+] (<50–100 nM), the PMCA is inactive and present in an auto-inhibited conformation in which the C-terminal tail makes intramolecular contacts with the A- and N-domains. Upon a rise in [Ca2+]i the PMCA is activated, and this activation is accelerated and enhanced by Ca2+-calmodulin, which binds to the auto-inhibitory tail and releases the inhibition. The effect of calmodulin thus is to shift the apparent Km(Ca2+) for activation of the PMCA to lower [Ca2+] (0.2–0.5 μM). Different isoforms and splice variants of the PMCA vary significantly in their calmodulin affinity and the speed with which they are activated. This is of physiological significance as “fast” PMCAs (such as PMCA2b) are generally found in “fast” cells (muscle, nerves) requiring rapid Ca2+ clearance after a spike. PMCAs are also regulated by acidic phospholipids such as phosphatidylserine and phosphatidylinositol, dimerization (oligomerization), phosphorylation on Ser/Thr residues in the regulatory tail, partial proteolysis of the auto-inhibitory tail by  calpain, as well as by specific protein interactions with regulatory proteins and the cytoskeleton (Strehler et al. 2007; Brini and Carafoli 2009; Strehler 2016). Multiple other regulatory interactions have also been demonstrated for various PMCA isoforms with proteins such as 14–3-3ε, Homer-2, calcineurin A, RASSF1, Grb2, α-1 syntrophin, and numerous signaling, trafficking, and anchoring proteins containing PDZ (PSD95/Dlg/ZO-1) domains. A scheme listing many PMCA-interacting proteins is shown in Fig. 4. It should be noted that several of these proteins interact specifically with some but not all PMCA isoforms and splice variants. For example, the a-splice variants of the PMCA lack a canonical PDZ-binding sequence motif at their C-terminus and are therefore unable to engage in PDZ domain-mediated interactions with other proteins.
Plasma Membrane Calcium-Transporting ATPase, Fig. 4

Proteins interacting with the PMCA, and their possible roles in PMCA regulation and function. PMCA-binding proteins are schematically shown as gray ovals near the domain(s) of the PMCA with which they interact. Known or suspected roles of these proteins in PMCA trafficking, regulation, and signaling are indicated in boxes beneath the listed proteins. The PMCA is schematically shown on the top, with the membrane-spanning segments numbered 1–10, and the N- and C-terminal ends labeled N and C, respectively. The two major sites of alternative splicing are also indicated, and the two main C-terminal splice variants “a” and “b” are shown with separate tails to indicate their sequence divergence. Note that PDZ domain-containing proteins can only bind to “b-type” splice variants of the PMCA and that not all PMCA isoforms interact with all of the listed proteins. Cytoskeletal proteins including actin, ankyrin, and tubulin may also interact directly with the PMCA, although the specific sites of interaction have not yet been unequivocally established

Tissue and Subcellular Expression

All tissues and cells express at least one isoform of the PMCA; however, multiple PMCA isoforms and splice variants are often found in the same cell. During (mouse) embryonic development, PMCA1 (splice variant 1x/b) is detected from the earliest time points studied and is expressed in most tissues throughout life. PMCA1 is thus considered a “housekeeping” PMCA isoform, although this only applies to splice variant 1x/b. PMCA1x/a and 1x/c are much more restricted in their expression and are mainly found in differentiated neurons and skeletal muscle cells. PMCA4x/b is also fairly ubiquitous, although there are large differences in PMCA4b expression among different tissues and cell types. By contrast, PMCAs 2 and 3 are almost exclusively found in excitable tissues including brain and muscle, as well as in secretory cells such as insulin-secreting pancreatic β-cells and lactating mammary epithelial cells (Strehler and Zacharias 2001). Some splice variants are highly specific for particular cells: PMCA2w/a, for example, is specifically and abundantly expressed in auditory and vestibular hair cells of the inner ear (Hill et al. 2006). Different PMCAs are often co-expressed in the same cell, where they are specifically targeted to distinct membrane compartments such as the apical or basolateral side of a polarized epithelial cell. This suggests that different PMCA isoforms fulfill distinct roles in global and local Ca2+ handling. In cochlear hair cells, for example, PMCA1x/b is expressed in the basolateral membrane, where it is involved in maintaining the low resting level of Ca2+ in the cell soma. In the same cells, PMCA2w/a is highly concentrated in the apical stereocilia, where it plays an important role in regulating [Ca2+] in the endolymph and modulating the function of the mechanotransduction channels. Some PMCA isoforms are also enriched in membrane domains of specific lipid composition (e.g., caveolae) where they associate with other signaling and transport proteins (Oceandy et al. 2011).

Functions in Health and Disease

In cells such as human erythrocytes, where the PMCA is the sole Ca2+ export system, the pump is obviously essential for normal Ca2+ homeostasis and cell physiology. However, because of its low abundance in most plasma membranes and its low capacity (maximal turnover of about 100 Ca2+ ions per second), the PMCA is generally not well suited for handling high global Ca2+ loads such as those occurring with each heart beat in a cardiac muscle cell. Conversely, due to its very high Ca2+ affinity (Kd < 0.2–0.5 μM) in the activated state, the PMCA is the only Ca2+ export system capable of lowering intracellular [Ca2+] to the very low resting levels (∼100 nM) normally found in most cells. In terms of global cellular Ca2+ homeostasis, the expression of different PMCA isoforms and splice variants allows cells to fine tune and maintain the specific Ca2+ set point optimal for their physiological function.

In tissues involved in transcellular Ca2+ transport, the PMCA (specifically, PMCA1b) plays an essential role in normal physiology. In kidney and intestinal epithelial cells, PMCA1b in the basolateral membrane is important for the vectorial transport of Ca2+ from the apical (lumenal) to the basal (blood) compartment and thus for Ca2+ (re)absorption. As may be expected, in these tissues the expression and localization of the PMCA are under hormonal control by vitamin D3 (Strehler 2016). Similarly, in the lactating mammary gland, the PMCA (isoform PMCA2w/b) is concentrated in the apical membrane of secretory epithelial cells and is essential for the export of Ca2+ into the (milk) lumen. Accordingly, female mice lacking PMCA2 produce Ca2+ deficient milk and their offspring are underweight (Reinhardt et al. 2004).

In addition to their roles in bulk vectorial Ca2+ transport, PMCAs are involved in the spatiotemporal control of Ca2+ signaling. Specific PMCA isoforms and splice variants are targeted to plasma membrane sub-compartments where they form multiprotein signaling complexes with adaptor proteins and other transporters and receptors to control local Ca2+ signals. By influencing the amplitude and recovery time of locally evoked Ca2+ spikes, the PMCAs contribute to the decoding of Ca2+ signals and affect the frequency of Ca2+ oscillations (Pászty et al. 2015). By reducing the spread of a local increase in Ca2+, they help suppress signaling “noise,” thereby increasing the fidelity and spatial resolution of Ca2+ signaling. Because of the pronounced differences in their kinetic and regulatory properties, different PMCA isoforms are adapted to handle very different Ca2+ signals ranging from slow, solitary Ca2+ waves to highly localized, high-frequency Ca2+ spikes such as those elicited at neuronal synapses. For example, specific PMCA2 splice variants play important roles in pre- and postsynaptic function such as in the regulation of excitatory synaptic transmission at hippocampal CA3 synapses or in short-term plasticity in cerebellar parallel fiber to Purkinje neuron connections. Deficiency of the corresponding PMCA leads to functional deficits such as impaired motor coordination (Huang et al. 2010; Brini et al. 2016). In general, other PMCA isoforms are unable to compensate for the deficiency in a specific isoform, supporting the notion of the highly defined functions that specific PMCAs assume in Ca2+ signaling.

Given its early expression during development and ubiquitous presence in all tissues, it is not surprising that PMCA1 ablation is embryonic lethal (Prasad et al. 2007). Heterozygous mice lacking one copy of the PMCA1 gene appear phenotypically normal, although they do show physiological differences from the wild type such as an increased stimulated peak tension of bladder smooth muscles and reduced bone mineral mass. Mutations in the human ATP2B1 (PMCA1) gene lead to specific disease phenotypes: Genome-wide association studies revealed a highly significant association of specific single-nucleotide polymorphisms (SNPs) in ATP2B1 with high systolic blood pressure and cardiovascular disease risk in humans.

Deletion of PMCA2 leads to profound deafness, ataxia, and various other deficiencies such as a decrease of milk calcium (as already mentioned above), reduced visual responses from retinal bipolar cells, and spinal cord pathology (Prasad et al. 2007). Even single point mutations affecting the function of PMCA2 can cause significant hearing impairment, underscoring the importance of the unique role of PMCA2w/a in auditory hair cell function. Mutations in the PMCA2 (ATP2B2) gene have been linked to human hearing loss; in the heterozygous state, they generally manifest in a more complex digenic inheritance pattern (Brini et al. 2016).

Loss of PMCA3 in mice was shown to be associated with increased sleep duration due to altered Ca2+-dependent hyperpolarization in neurons involved in the regulation of sleep homeostasis. In contrast, missense mutations in human ATP2B3 (PMCA3) have been linked to X-linked congenital cerebellar ataxia and to developmental delay, hypotonia, and ataxia in a case with concomitant mutations in the laminin 1α gene. These findings are in agreement with the predominant expression of PMCA3 in the brain and an important function of this isoform in cerebellar neurons. Somatic PMCA3 mutations resulting in impaired pump function have also been detected in several cases of human aldosterone-producing adenomas (and secondary hypertension), pointing to an important role for this pump in the regulation of membrane polarization (Brini et al. 2016).

In mice, knockout of the PMCA4 (Atp2b4) gene results in viable animals without overt gross abnormalities. However, males are infertile due to a defect in sperm hyperactivated motility, which is apparently dependent on PMCA4 normally concentrated in the sperm tail (Prasad et al. 2007). Lack or altered expression of PMCA4 also leads to changes in cardiac physiology, such as altered response to beta-adrenergic stimulation and change in blood pressure, reinforcing the notion of the PMCA4 as an important signaling molecule rather than as general “sump pump” to remove global Ca2+ (Holton et al. 2010). A missense mutation in the human PMCA4 (ATP2B4) gene has been shown to be a causative for a form of autosomal dominant familial spastic paraplegia in a Chinese family pedigree, suggesting that similar to PMCA2 and PMCA3, PMCA4 also fulfills specialized functions in distinct neuronal cells (Li et al. 2014).

Considering the universal importance of Ca2+ signaling, it is no surprise that numerous diseases are characterized by altered expression and/or impaired function of specific PMCAs. Systemic disease as well as tissue-specific disorders can be caused by deficiency of a single PMCA isoform. Because the PMCAs are functionally integrated in multi-protein signaling complexes, any disturbance of such complexes can have disease-causing consequences. Major diseases that show distinct changes in PMCA isoform expression and function include diverse cancers, neurodegenerative disorders such as Alzheimer’s and Huntington’s disease, and diabetes (Lehotsky et al. 2002; Brini and Carafoli 2009). However, in many cases, it is not clear whether aberrant PMCA expression and/or function is causative or reflects a secondary (potentially compensatory) reaction to a different primary insult.

Summary

Plasma membrane Ca2+-transporting ATPases (PMCAs) are essential components of the calcium signaling toolkit of eukaryotic cells. These membrane-embedded transporters couple the expulsion of 1 Ca2+ ion to the hydrolysis of 1 ATP and attain maximal rates of about 100 Ca2+ transported per second. PMCAs are the major high-affinity Ca2+ export system dedicated exclusively to the export of Ca2+ from cells and are essential for the maintenance of the steep [Ca2+] concentration gradient that is a prerequisite for the high specificity and fidelity of Ca2+ signaling. In mammals, four genes encode PMCAs 1–4; alternative RNA splicing augments the number of distinct isoforms to over 30. The PMCAs are highly regulated by multiple mechanisms including Ca2+-calmodulin, acidic phospholipids, phosphorylation, oligomerization, and interactions with numerous signaling, targeting, and anchoring proteins. PMCA isoforms and splice variants show developmental, tissue- and cell type-specific expression, and are targeted to specific membrane compartments where they contribute to local Ca2+ handling. PMCA isoforms show characteristic differences in kinetic and regulatory properties, providing cells with many options to deploy specific PMCAs to distinct plasma membrane compartments with different Ca2+ signaling needs. Consistent with a role in local Ca2+ handling, deletion, mutation, or altered expression of specific PMCAs causes characteristic cellular defects. Deletion of the ubiquitously expressed PMCA1 results in embryonic lethality, whereas mutations in the PMCA1 gene are associated with systolic hypertension and cardiovascular disease risk. Mice lacking PMCA4 are superficially normal but show altered cardiac stress responses and are male-infertile due to impaired sperm motility; in humans a PMCA4 missense mutation leads to autosomal dominant familial spastic paraplegia. Deletion or mutation of PMCA2 results in hearing loss, balance and vision defects, ataxia, spinal cord pathology, as well as reduced milk calcium. Cerebellar ataxia and altered sleep regulation are among the consequences of mutation or the lack of expression of PMCA3. PMCAs are now being recognized as major players in spatiotemporal Ca2+ signaling with specific involvement in diverse cell functions, and are potential targets for intervention in the treatment of various diseases linked to abnormal Ca2+ handling.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyMayo Clinic College of Medicine and ScienceRochesterUSA
  2. 2.Department of BiomedicineUniversity of BaselBaselSwitzerland