THE ROLE OF PLASMA MEMBRANE Ca2+-ATPase IN EXCITABLE CELLS SIGNALING



Ludmila Zylinska

Neurochemical Laboratory, Department of Biochemistry, Medical University. Lodz, Poland

Address for correspondence:
Ludmila Zylinska
Neurochemical Laboratory
Department of Biochemistry
Medical University
6 Lindley Street
90-131 Lodz, Poland
phone : (+48.42) 679.00.35
fax : (+48.42) 678.62.45
E-mail : luska@psk2.am.lodz.pl
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Abstract
Introduction
Localization of plasma membrane Ca2+-ATPase isoforms in the brain
Regulation of calcium pump by phosphorylation processes
Regulation of Ca2+-ATPase by neuroactive steroids
Anesthetics effect on Ca2+-ATPase
Modification of Ca2+-ATPase function by reactive oxygen species
Conclusion
References

Abstract

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During the last decade the mechanisms of Ca2+ regulation in the brain have been extensively investigated in a variety of neural cells. These investigations demonstrate that intraneuronal Ca2+ participate in the multiple controls of important neural functions, like excitability, neurotransmitters release or long-term changes in synaptic efficacy. Moreover, there is a significant number of data confirming that the impairment of calcium homeostasis is closely linked with aging and several brain disorders. The plasma membrane Ca2+-ATPase (PMCA) is a ubiquitously expressed protein, which constitutes a high affinity system extruding Ca2+ outside the cell and maintains the intracellular Ca2+ in the submicromolar range in a resting state. In neuronal tissues more than 26 transcripts of the four separate PMCA genes are distributed in a region specific manner. Differences in the structure and localization of PMCA variants are thought to correlate with specific regulatory properties and may have consequences for proper Ca2+ signaling or for the response to the brain malfunction. Below some new aspects of the Ca2+-ATPase modulation in physiological and pathological conditions will be discussed which may influence neuronal calcium signaling.
 

Key words: plasma membrane Ca2+-ATPase, brain, regulation, pathology, calcium homeostasis.

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Introduction
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Calcium ions are the most ubiquitous signal transduction elements in cells, which in cytosol is maintained at a very low level. In resting neuronal cells the concentration of [Ca2+]i is near or below 100 nM, and depolarization of the membrane can increase it to 1 mM. The external calcium concentrations range from 1—2 mM, yielding the chemical gradient up to 40 000:1 [7]. The generation of a Ca2+ signal in neurons occurs in more than one way. In membranes due to conformational changes in Ca2+-selective voltage-dependent channels, Ca2+ level increases within milliseconds, and initiates further events by a depletion of intracellular, multiregulated Ca2+ stores [32].

In the mammalian nervous system the large fluctuations in extracellular calcium levels are part of normal neural activities which are closely connected with intraneuronal processes, including production of a broad array of messengers, gene regulation, modulation of ion channels, and activation of enzymes. The synaptic transmission is modulated by the activity of enzymes, which are regulated by Ca2+, and by the activity of pumps and transporters, which maintain intracellular calcium homeostasis. Calcium efflux from neuronal cells occurs through two main systems — an electrochemically driven Na+/Ca2+ exchanger with a low Ca2+ affinity (K0.5 = 10-15 mM), and a plasmalemmal, specific Ca2+-ATPase, with a high Ca2+ affinity (K0.5 < 0.5-1 mM) [17]. The capacity of Na+/Ca2+ exchanger to pump out calcium ions is more than 10 times greater when compared to the plasma membrane Ca2+-ATPase. However, the calcium pump has been postulated to play a specific role in fine-tuning Ca2+ levels and maintain it in neural cell at nanomolar concentrations.

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Localization of plasma membrane Ca2+-ATPase isoforms in the brain

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Multiple PMCA isoforms are coded by four different genes (PMCA 1 - 4), and due to alternative mRNA splicing at four possible sites (A, B, C and D) more than 26 variants can exist [21]. PMCA1 and 4 are expressed in practically all tissues, and PMCA2 and 3 have been shown to occur in highly specialized tissues, especially in the brain. It is noteworthy that the brain contains up to 10 times more PMCA than nonexcitable cells. During the past several years, the primary structure of a number of PMCA isoenzymes potentially existing in the brain have been determined by molecular cloning techniques [18 for review]. The analysis of fourteen subregions of a normal human brain by RT-PCR has shown a different distribution of the four PMCA genes and their splicing variants [42]. In human hippocampus the mRNAs expression pattern differed throughout the hippocampal formation [43]. There is also evidence that kainate-induced neurodegeneration of the hippocampal subfields altered the PMCAs at the mRNA and protein levels, which could be an important factor for Ca2+ dyshomeostasis [16]. Using in situ hybridization and isoform specific monoclonal antibodies it was demonstrated that mRNAs, and PMCA proteins were also nonuniformly distributed in different regions of rat, pig and gerbil brains [11, 24, 35, 37, 38]. In rat cultured cerebellar granule cells the expression of the PMCA1, 2 and 3 isoforms has become up-regulated, whereas PMCA4 isoform was down-regulated during the maturation process, and dependent on increased Ca2+ concentration [19]. These changes are likely to reflect the specific functional Ca2+ pumping requirements of the cell during development. An electron microscopic cytochemical study has shown that in the rat brain the Ca2+-ATPase was associated with synaptic membranes, and only neurons were PMCA positive [37]. The unique pattern of PMCA isoforms, confirmed independently by several laboratories, is critical for understanding functional diversity of rat brain areas, because now it is well-established that alternative splicing of the A and C sites has a large effect on the regulatory properties of the calcium pump. The specific PMCA localization appears to be primarily related to the involvement of specific Ca2+ signaling in the regulation of transduction and adaptation mechanisms. In cells the activity of the calcium pump could be modified by a large number of regulatory mechanisms. These include stimulation by calmodulin (CaM), acidic phospholipids, protein kinases, proteolysis or self-association [28 for review]. These regulations were described for the first time more than 10-15 years ago, but further extensive studies have revealed more details of the molecular mechanisms of these processes, particularly in the brain. Some of them will be discussed below.
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Regulation of calcium pump by phosphorylation processes

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Activation of calcium pump by protein kinases A and C has been reported in a variety of cells [28]. The phosphorylation of Ser and Thr was previously demonstrated in purified red blood cell Ca2+-ATPase phosphorylated with rat brain type III protein kinase C (PKC). Experiments with a synthetic peptide, corresponding to the calmodulin-binding domain of the pump, have shown that PKC phosphorylated the threonine residue, and recent studies have demonstrated that at least one serine residue located carboxy-terminally to the CaM-binding domain was the substrate for this kinase. Up to now, only partial data have been published on the possible regulation of the calcium pump by phosphorylation processes in the nervous tissue [23, 44]. In PMCA variants the sequences phosphorylated by protein kinases are not conserved and phosphorylation could differently regulate the calcium pump activity. In brain serine/threonine protein kinases-mediated phosphorylation of Ca2+-ATPase appears to be physiologically significant, since phosphoserine and phosphothreonine have been detected in the enzyme purified from rat cortex, cerebellum and hippocampus [44]. Although the nature of protein kinases that phosphorylate the Ca2+-ATPase in vivo is not known, this indicates that phosphorylation is a naturally existing process in neuronal cells. Moreover, the purified enzyme was a substrate for protein kinases A and C in vitro. PKC belongs to the kinase family consisting of at least 11 closely related isoenzymes which exhibit distinct tissue distribution and some substrates are phosphorylated by calcium-dependent isoenzymes of PKC, whereas the others are good substrates for calcium-independent ones. This specificity could be therefore crucial for the efficiency of Ca2+-induced signaling events in vivo, as well as for the maintenance of calcium homeostasis in the nervous cell. The study performed with isoform PMCA2 and PMCA3 variants which were expressed in COS cells revealed that PKC regulated their activity in different way [8]. Little or no phosphorylation by PKC was detected in PMCA2b and PMCA3b forms, whereas PMCA2a and PMCA3a variants were phosphorylated, however without increasing the Ca2+ transport activity. The phosphorylation process prevented stimulation of Ca2+-ATPase by calmodulin, and the authors suggest that PKC, by the inhibition of the activity of these isoforms, could allow Ca2+ to increase inside the cell. The phosphorylation of PMCA4a isoform was blocked when CaM was bound to the enzyme, but the phosphorylation of the pump in the absence of CaM did not eliminate both further activation by CaM and binding to CaM-Sepharose [41]. From the experiments performed with overexpressed pump isoforms in COS cell membranes, 2a, 3a, 4a and 4b were phosphorylated by PKC, but only 4b was activated by this process. However, the physiological importance of these regulations for the brain is still unresolved.

The phosphorylation of brain Ca2+-ATPase by protein kinase A has not been examined in detail. In erythrocytes, PKA was described to phosphorylate the serine residues located to the calmodulin-binding domain of PMCA1 isoform [28]. On the other hand, using reverse transcription followed by PCR, Khan and Grover have reported the existence in the brain of isoform PMCA1 potentially insensitive to PKA [22]. In comparison to other rat tissues, the transcripts encoding the potentially PKA-insensitive PMCA1 isoform in the brain comprised about 50 %. In line with these results it could be assumed that the PMCA1-immunoreactivity expressed in particular regions or even layers of brain regions could be closely related with the specific brain functions. The activity of Ca2+-ATPase purified from rat cortex, cerebellum and hippocampus was enhanced after incubation with protein kinase A in a region-dependent manner, which could be related to isoforms variability in the diverse areas of the rat brain. [44]. Protein kinase A-mediated phosphorylation of Ca2+-ATPase could have physiological consequences on neuronal cells, since protein kinase A can be activated independently of intracellular calcium concentration. A possible hypothesis is that the calcium pump can exist in a phosphorylated state, dependent on the net intracellular phosphatases and kinases activities, which are regulated by several second messenger-operating systems.

The phosphorylation processes could also modify the calcium pump activity indirectly, because another physiological target for protein kinases is CaM. The regulatory properties of this naturally existing activator of the calcium pump are changed by the phosphorylation processes. CaM is known to be phosphorylated in vivo and in vitro by several serine/threonine-protein and tyrosine-protein kinases, i.e. casein kinase II, insulin-receptor kinase, epidermal-growth-factor-receptor tyrosine kinase or phosphorylase kinase [3, 4, 31]. Phosphocalmodulin has been identified in several intact cells and tissues, and in some cells approximately 15 % of CaM could be in phosphorylated state [31]. It has been demonstrated that phosphorylation of calmodulin on serine/threonine residues resulted in the diminished potency for activation of the erythrocyte calcium pump, whereas tyrosine phosphorylation did not significantly modify its interaction with the calcium pump [31, 34]. Since calmodulin is involved in the regulation of a great number of the enzymes, and in the brain the activities of protein kinases and phosphatases are very high, the phosphorylation of CaM could be an important factor in the modulation of the neural CaM-mediated processes.

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Regulation of Ca2+-ATPase by neuroactive steroids

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One of the newer insights concerning the regulatory mechanism of the brain Ca2+-ATPase function is the influence of direct and indirect modulation by the neuroactive hormones. The prevailing classical hypotheses for the mechanism of steroid hormones regulation postulate their genomic action. Recently, the plasma membrane has been extensively studied as a possible site of steroids binding [1]. The insertion of steroids into the proteins/lipids bilayer may alter the architecture of the membrane, with consequences for the plasma membrane enzyme activities. Moreover, neuroactive steroids are also able to modify directly the neuronal membrane composition by initiating the phospholipid turnover, and thereby affecting the fluidity of the membrane [40]. The multistep action of neuroactive steroids seems to be physiologically relevant because some of them can be synthesized and accumulated in the central nervous system, independently of peripheral sources [25]. Thus, the nervous cell appears to be under permanent short and long-term control of steroids. The rapid effects induced by neuroactive steroids at the plasma membrane level could be a kind of chemical signaling which regulate the brain function. Very little is known about the possible role of steroid hormones in the regulation of PMCA activity. In synaptosomal membranes of the dog brain, testosterone increased the activity of Ca2+-stimulated ATPase, whereas progesterone revealed the opposite effect [6]. In the rat brain the observation was originally made on neuronal membrane preparations in which the increasing activity of the Ca2+-ATPase after short-time incubation with physiologically relevant concentration of pregnenolone sulphate and 17-b-estradiol was observed [45]. Later, experiments with purified rat cortical Ca2+-ATPase suggested that neuroactive steroids, 17-b-estradiol, testosterone, pregnenolone sulfate and dehydroepiandrosterone sulfate, were responsible for the direct modulation of the Ca2+-ATPase hydrolytic activity [46]. It should be noted that in both types of experiments, stimulation of the calcium pump at biologically important concentrations (pM to nM) of neuroactive steroids has been observed. Differences in functional properties of the plasma membrane Ca2+-ATPase induced by neuroactive steroids could be attributed to direct binding to the enzyme molecules, rather than to changes in membrane protein/lipid interaction. All examined neuroactive steroids decreased also the calmodulin stimulation of Ca2+-ATPase. More importantly, they were more effective than CaM in the activation of purified Ca2+-ATPase. It could suggest that the presence of steroids disturbed the interaction of CaM with the enzyme, and the CaM-binding domain of Ca2+-ATPase could be a primary site of steroids action. These observations may have physiological consequences, because a local steroid synthesis could allow permanent, Ca2+-independent regulation of Ca2+-ATPase activity in neuronal plasma membranes, whereas the binding of calmodulin is a Ca2+-dependent process. Thus, the plasma membrane enzyme appears to be a target site for neuroactive steroid action at biologically relevant concentrations, and the structural differences of the steroids could be a critical determinant of the steroids-calcium pump interaction. These results postulate the existence of a novel, distinct mechanism of Ca2+-ATPase regulation, but the physiological evidence concerning the mechanisms and importance of non-genomic regulation Ca2+-ATPase by steroid hormones in nervous tissue are still quite limited, and much more experimental data are needed.
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Anesthetics effect on Ca2+-ATPase

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The neuronal transmission could be also altered by the interference of some chemical compounds, like inhalation anesthetics, with a plasma membrane. Recently, a susceptibility of the calcium pump to anesthetics has been extensively examined by several laboratories. The anesthetics have been shown to perturb the process of extruding Ca2+ through the plasma membrane by the inhibition of PMCA in brain synaptic membranes, and in cultured cells of neural origin [13, 14]. The activity of Ca2+-ATPase in cerebral and cerebellar synaptosomal membranes was diminished in a dose-dependent fashion during an exposure in vitro to halothane, isoflurane, xenon and nitrous oxide at clinically relevant concentration. Moreover, the decrease in anesthetic requirements was associated with aging which can suggest that the alteration of Ca2+ homeostasis in aging brain may interfere with the neurotransmitter release and alter the intraneuronal signaling [20]. Similar inhibition patterns of PMCA by halothane and isoflurane at anesthetic concentration were observed in red blood cells and rat synaptosomal membranes [12]. A new sight on the anesthetic action has been proposed by Pflugmacher and Sandermann [30]. Basing on the multiple-site kinetics analysis of the synaptosomal Ca2+-ATPase inhibition by the selected organic solvents and anesthetics, the authors have concluded that the lipid/protein interface rather than protein or lipid alone could be a target site for anesthetics action. Although they have observed an inhibition of the Ca2+-ATPase activity by a high concentration of ethanol (I50 = 350 mM), there is some evidence indicating that in erythrocytes a lower ethanol concentration (up to 0.5 %) stimulated the activity of the enzyme [2]. These results are of interest because ethanol, due to the transphosphatidylation process, could form phosphatidylethanol, which in turn as a negatively charged phospholipid, may affect the structural architecture of the membranes. In addition, phosphatidylethanol has been shown to produce a twofold stimulation of Ca2+-ATPase activity in erythrocytes [39]. In contrast with other acidic phospholipids i.e. phosphatidylserine, the effects of Ca2+-ATPase activation by CaM and phosphatidylethanol were additive. More importantly, ethanol has been shown to activate the calcium pump in an isoform-specific manner [5]. The most susceptible isoform was PMCA2CI, the particularly abundant isoform in the brain, which was already activated by 0.1-0.2 % ethanol.
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Modification of Ca2+-ATPase function by reactive oxygen species

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Now it is widely accepted that disturbances in calcium homeostasis play an important role in a brain damage, and the redox state of the neuronal cell has been shown to dramatically influence the cytosolic Ca2+ metabolism [27]. A number of processes that have been implicated in the Ca2+ related pathogenesis included brain aging, ischemia/anoxia, oxidative stress, as well as some brain disorders i.e. Alzheimer disease or Parkinson disease. The brain contains source of oxidative stress unique to this tissue. During hypoxia/ischemia, the conditions with decreased cellular high energy levels, the amino acids neurotransmitter — glutamate and aspartate, as well as their derivatives, can trigger a series of events due to production of the reactive oxygen species (ROS), leading to neuronal damage and death. ROS can react with unsaturated fatty acids, amino acid residues (Cys, Met, Tyr), and purine bases, and the oxidative modification is particularly more pronounced during hypoxia/ischemia cell injury. The deleterious effect of the free radicals has been reported to disturb ion permeability and to change the protein-lipid interactions. Perturbation of calcium signaling could be significantly altered by the membrane lipids peroxidation processes. It is well-documented that Ca2+-ATPase can be shifted to the high-affinity state by acidic phospholipids, as well as polyunsaturated fatty acids [28]. One of the most potent lipids activator of Ca2+-ATPase is phosphatidylserine. Recently, Fabisiak et al. have observed that after exposition of different classes of phospholipids to free radicals, only phosphatidylserine was not protected against peroxidation by the vitamin E analog [9]. One could speculate that the peroxidation of phosphatidylserine, which constitute about 30 % of the total phospholipids in the membrane, could have profund consequences in a proper Ca2+-ATPase functioning.

There is also some evidence indicating that reactive oxygen species have influenced the plasma membrane calcium pump function. Ca2+-ATPase has showed diminished activity following ascorbate/iron induced oxidation, and a similar effect has been observed after Fe2+/H2O2 incubation [29, 33]. Erythrocyte membranes exposed to peroxynitrite have shown aggregation and nitration of proteins, changes in protein organization, and inactivation of the Ca2+- ATPase activity [36]. Thus, the decreased activity could result from both, alteration of the lipid environment and the direct modification of the polypeptide chain.

Among the proteins modified during oxidative stress, calmodulin has been identified as potentially relevant for ROS action [15, 26]. Calmodulin in the brain is estimated to reach approximately 30 mM, and its binding to Ca2+-ATPase can shift affinity for calcium below 0.5 nM, and can increase the maximal velocities of Ca2+ transport several times. CaM contains a number of methionone residues (about 6 % of the total amino acids in calmodulin), and these amino acids play a critical role in the binding of CaM to target proteins, including Ca2+-ATPase. Using the mass spectrometry and amino acid analysis the oxidative modification of the methionone residues after in vitro ROS action has been detected. Also a decreased ability of CaM to activate the calcium pump has been observed in the aging brain. Since methionine is particularly prone to oxidative modification, under the oxidative stress the extrussion of the Ca2+ could become diminished. Both CaM and Ca2+-ATPase exhibited functional defects, which could be a result of accumulated oxidative events occuring during the cell life. From experimental data the apparent half-lives for CaM and PMCA were 18 ± 2 hours and 12 ± 1 days, respectively [10]. However, despite the rapid turnover of CaM in the brain, a remarkable degree of protein modification, i.e. oxidated methionine, has been observed. This may suggest that these CaM modifications could be of both physiological and pathological relevance.

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Conclusion

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Elevated Ca2+ in neurons initiate a cascade of signaling which in physiological conditions is an integral part of the functioning of the excitable cells. The fluctuation of Ca2+ concentration regulated in several ways and the maintenance of calcium homeostasis are crucial elements of the cellular strategy to prevent damage and cell death. Plasma membrane Ca2+-ATPase appears to be a particularly important regulator of the Ca2+ signaling system. The complexity of the neural processes as well as the multiple role of the calcium ions have given a new perspective for calcium pump role in the physiological and pathological conditions in the brain.
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Acknowledgments
This work was supported by the grants No. 502-11-558 and No. 503 from Medical University of Lodz.

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