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See detailPhysiological implications of the interaction between the plasma membrane calcium pump and nNOS.
Cartwright, Elizabeth J.; Oceandy, Delvac; Neyses, Ludwig UL

in Pflugers Archiv : European journal of physiology (2009), 457(3), 665-71

The tight regulation of intracellular calcium levels is essential for the normal function of a great many cellular processes, and disruption of this regulation, resulting in sustained increases in ... [more ▼]

The tight regulation of intracellular calcium levels is essential for the normal function of a great many cellular processes, and disruption of this regulation, resulting in sustained increases in intracellular-free calcium, has been associated with numerous diseases. One of the several transporters involved in calcium homeostasis is a P-type ATPase known as the plasma membrane calcium/calmodulin-dependent ATPase (PMCA) which is involved in calcium extrusion from the cytosol to the extracellular compartment. It has long been established that in many cell types, in particular non-excitable cells, the primary role of PMCA is in the bulk transport of intracellular calcium; however, its role in excitable cells is less clear. In the heart, for example, calcium is essential for contractile function as well as being a key messenger in signal transduction pathways; however, the mechanisms by which the cardiomyocyte distinguishes between these roles of calcium remain unclear. It is perhaps the transporters not involved in the contractile cycle (such as PMCA) that are able to carry non-contractile signals. This review will highlight the role of PMCA as a modulator of signal transduction pathways and in particular the role of isoform 4 in the regulation of the nitric oxide signalling pathway. [less ▲]

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See detailCardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth.
Liu, Wei; Zi, Min; Jin, Jiawei et al

in Circulation Research (2009), 104(7), 905-14

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen ... [more ▼]

Mitogen-activated protein kinase kinase (MKK)4 is a critical member of the mitogen-activated protein kinase family. It is able to activate the c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase in response to environmental stresses. JNK and p38 are strongly implicated in pathological cardiac hypertrophy and heart failure; however, the regulatory mechanism whereby the upstream kinase MKK4 activates these signaling cascades in the heart is unknown. To elucidate the biological function of MKK4, we generated mice with a cardiac myocyte-specific deletion of mkk4 (MKK4(cko) mice). In response to pressure overload or chronic beta-adrenergic stimulation, upregulated NFAT (nuclear factor of activated T-cell) transcriptional activity associated with exacerbated cardiac hypertrophy and the appearance of apoptotic cardiomyocytes were observed in MKK4(cko) mice. However, when subjected to swimming exercise, MKK4(cko) mice displayed a similar level of physiological cardiac hypertrophy compared to controls (MKK4(f/f)). In addition, we also discovered that MKK4 expression was significantly reduced in heart failure patients. In conclusion, this study demonstrates for the first time that MKK4 is a key mediator which prevents the transition from an adaptive response to maladaptive cardiac hypertrophy likely involving the regulation of the NFAT signaling pathway. [less ▲]

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See detailPromoter polymorphism of the matrix metalloproteinase 3 gene is associated with regurgitation and left ventricular remodelling in mitral valve prolapse patients.
Oceandy, Delvac; Yusoff, Rahal; Baudoin, Florence M. et al

in European journal of heart failure (2007), 9(10), 1010-7

BACKGROUND AND AIMS: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that ... [more ▼]

BACKGROUND AND AIMS: Mitral valve prolapse (MVP) is common and highly variable in its severity, but the factors underlying this variability are unclear. In this study, we tested the hypothesis that polymorphic variations in Matrix Metalloproteinase (MMP) genes might be predictors of left ventricular (LV) remodelling and severity of regurgitation in MVP. METHODS AND RESULTS: 70 MVP patients and 75 normal subjects were studied. We performed comprehensive echocardiography and analyzed promoter polymorphisms in the MMP-1 and MMP-3 genes. The MMP-3 -1612 5A/6A polymorphism showed strong associations with indices of mitral regurgitation and LV remodelling: Patients with 5A/5A allele had more pronounced remodelling and more severe mitral regurgitation than patients with the 6A/6A or 5A/6A alleles. We then cloned and sequenced 2 kb fragments of MMP-3 promoter from patients with 5A/5A and 6A/6A genotypes and found 4 different sets of promoter haplotypes. Promoter analysis showed that higher promoter activity was related to a more severe phenotype and that the haplotype variants had a more dominant role in determining the activity. CONCLUSIONS: Our data identifies the MMP-3 promoter haplotype as a novel marker of an adverse disease course in MVP, suggesting the presence of genetic determinants for the severity of MVP. [less ▲]

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See detailPlasma membrane calcium ATPase and its relationship to nitric oxide signaling in the heart.
Cartwright, Elizabeth J.; Oceandy, Delvac; Neyses, Ludwig UL

in Annals of the New York Academy of Sciences (2007), 1099

The plasma membrane calcium/calmodulin-dependent ATPase (PMCA) is a ubiquitously expressed calcium-extruding enzymatic pump. In the majority of cells the main function of PMCA is as the only system to ... [more ▼]

The plasma membrane calcium/calmodulin-dependent ATPase (PMCA) is a ubiquitously expressed calcium-extruding enzymatic pump. In the majority of cells the main function of PMCA is as the only system to extrude calcium from the cytosol, however, in the excitable cells of the heart it has only a minor role in the bulk removal of calcium compared to the sodium-calcium exchanger. There is increasing evidence to suggest that PMCA has an additional role as a potential modulator of a number of signal transduction pathways. Of key interest in the heart is the functional interaction between the calcium/calmodulin-dependent enzyme neuronal nitric oxide synthase (nNOS) and isoform 4 of PMCA. Nitric oxide production from nNOS is known to be important in the regulation of excitation-contraction (EC) coupling and subsequently contractility. This article will focus on recent evidence suggesting that PMCA4 has a regulatory role in the nitric oxide signaling pathway in the heart. [less ▲]

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See detailNeuronal nitric oxide synthase signaling in the heart is regulated by the sarcolemmal calcium pump 4b.
Oceandy, Delvac; Cartwright, Elizabeth J.; Emerson, Michael et al

in Circulation (2007), 115(4), 483-92

BACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the ... [more ▼]

BACKGROUND: Neuronal nitric oxide synthase (nNOS) has recently been shown to be a major regulator of cardiac contractility. In a cellular system, we have previously shown that nNOS is regulated by the isoform 4b of plasma membrane calcium/calmodulin-dependent ATPase (PMCA4b) through direct interaction mediated by a PDZ domain (PSD 95, Drosophilia Discs large protein and Zona occludens-1) on nNOS and a cognate ligand on PMCA4b. It remains unknown, however, whether this interaction has physiological relevance in the heart in vivo. METHODS AND RESULTS: We generated 2 strains of transgenic mice overexpressing either human PMCA4b or PMCA ct120 in the heart. PMCA ct120 is a highly active mutant form of the pump that does not interact with or modulate nNOS function. Calcium was extruded normally from PMCA4b-overexpressing cardiomyocytes, but in vivo, overexpression of PMCA4b reduced the beta-adrenergic contractile response. This attenuated response was not observed in ct120 transgenic mice. Treatment with a specific nNOS inhibitor (N omega-propyl-L-arginine) reduced the beta-adrenergic response in wild-type and ct120 transgenic mice to levels comparable to those of PMCA4b transgenic animals. No differences in lusitropic response were observed in either transgenic strain compared with wild-type littermates. CONCLUSIONS: These data demonstrate the physiological relevance of the interaction between PMCA4b and nNOS and suggests its signaling role in the heart. [less ▲]

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See detailTargeting the sarcolemmal calcium pump: a potential novel strategy for the treatment of cardiovascular disease.
Oceandy, Delvac; Mamas, Mamas A.; Neyses, Ludwig UL

in Cardiovascular & hematological agents in medicinal chemistry (2007), 5(4), 300-4

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified ... [more ▼]

Intracellular calcium dynamics play a very important role in mediating contraction and signalling in cardiomyocytes and vascular smooth muscle cells. A number of calcium transporters have been identified that orchestrate a complex process of excitation-contraction coupling and molecular signalling. Despite the variability of the calcium transporters expressed in cardiomyocytes, most calcium channel blockers used therapeutically target the L-type calcium channel and exhibit antihypertensive and/or vasodilating activities. Recently, another calcium pump which is located in the sarcolemma has been shown to mediate cardiac contractility and vascular tone. Interestingly, this sarcolemmal calcium pump (also known as Plasma Membrane Calcium/calmodulin dependent ATPase or PMCA) exerts its function not by altering global calcium concentration, but by mediating signal transduction pathways. This review will discuss recent advances that support the key roles of PMCA as signalling molecule and the potential to target this calcium pump as a novel approach for the treatment of cardiovascular disease. [less ▲]

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See detailThe emergence of plasma membrane calcium pump as a novel therapeutic target for heart disease.
Oceandy, Delvac; Buch, Mamta H.; Cartwright, Elizabeth J. et al

in Mini reviews in medicinal chemistry (2006), 6(5), 583-8

The plasma membrane calcium/calmodulin dependent ATPase (PMCA) is a calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. PMCA is the only system for calcium ... [more ▼]

The plasma membrane calcium/calmodulin dependent ATPase (PMCA) is a calcium-extruding enzymatic pump important in the control of intracellular calcium concentration. PMCA is the only system for calcium extrusion in the majority of cells. In excitable cells such as cardiomyocytes however, PMCA has been shown to play only a minor role in calcium homeostasis. In these cells the main mechanism of calcium extrusion is the sodium calcium exchanger. However, increasing evidence points to an important role for PMCA in signal transduction; in particular in the nitric oxide signalling pathway. In this review we will discuss recent advances that support a key role for PMCA in signal transduction and the potential for therapeutic targeting of this molecule in the treatment of cardiac diseases. [less ▲]

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See detailThe sarcolemmal calcium pump, alpha-1 syntrophin, and neuronal nitric-oxide synthase are parts of a macromolecular protein complex.
Williams, Judith C.; Armesilla, Angel L.; Mohamed, Tamer M. A. et al

in The Journal of biological chemistry (2006), 281(33), 23341-8

The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of ... [more ▼]

The main role of the plasma membrane Ca2+/calmodulin-dependent ATPase (PMCA) is in the removal of Ca2+ from the cytosol. Recently, we and others have suggested a new function for PMCA as a modulator of signal transduction pathways. This paper shows the physical interaction between PMCA (isoforms 1 and 4) and alpha-1 syntrophin and proposes a ternary complex of interaction between endogenous PMCA, alpha-1 syntrophin, and NOS-1 in cardiac cells. We have identified that the linker region between the pleckstrin homology 2 (PH2) and the syntrophin unique (SU) domains, corresponding to amino acids 399-447 of alpha-1 syntrophin, is crucial for interaction with PMCA1 and -4. The PH2 and the SU domains alone failed to interact with PMCA. The functionality of the interaction was demonstrated by investigating the inhibition of neuronal nitric-oxide synthase-1 (NOS-1); PMCA is a negative regulator of NOS-1-dependent NO production, and overexpression of alpha-1 syntrophin and PMCA4 resulted in strongly increased inhibition of NO production. Analysis of the expression levels of alpha-1 syntrophin protein in the heart, skeletal muscle, brain, uterus, kidney, or liver of PMCA4-/- mice, did not reveal any differences when compared with those found in the same tissues of wild-type mice. These results suggest that PMCA4 is tethered to the syntrophin complex as a regulator of NOS-1, but its absence does not cause collapse of the complex, contrary to what has been reported for other proteins within the complex, such as dystrophin. In conclusion, the present data demonstrate for the first time the localization of PMCA1b and -4b to the syntrophin.dystrophin complex in the heart and provide a specific molecular mechanism of interaction as well as functionality. [less ▲]

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See detailThe sarcolemmal calcium pump inhibits the calcineurin/nuclear factor of activated T-cell pathway via interaction with the calcineurin A catalytic subunit.
Buch, Mamta H.; Pickard, Adam; Rodriguez, Antonio et al

in The Journal of biological chemistry (2005), 280(33), 29479-87

The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma ... [more ▼]

The calcineurin/nuclear factor of activated T-cell (NFAT) pathway represents a crucial transducer of cellular function. There is increasing evidence placing the sarcolemmal calcium pump, or plasma membrane calcium/calmodulin ATPase pump (PMCA), as a potential modulator of signal transduction pathways. We demonstrate a novel interaction between PMCA and the calcium/calmodulin-dependent phosphatase, calcineurin, in mammalian cells. The interaction domains were located to the catalytic domain of PMCA4b and the catalytic domain of the calcineurin A subunit. Endogenous calcineurin activity, assessed by measuring the transcriptional activity of its best characterized substrate, NFAT, was significantly inhibited by 60% in the presence of ectopic PMCA4b. This inhibition was notably reversed by the co-expression of the PMCA4b interaction domain, demonstrating the functional significance of this interaction. PMCA4b was, however, unable to confer its inhibitory effect in the presence of a calcium/calmodulin-independent constitutively active mutant calcineurin A suggesting a calcium/calmodulin-dependent mechanism. The modulatory function of PMCA4b is further supported by the observation that endogenous calcineurin moves from the cytoplasm to the plasma membrane when PMCA4b is overexpressed. We suggest recruitment by PMCA4b of calcineurin to a low calcium environment as a possible explanation for these findings. In summary, our results offer strong evidence for a novel functional interaction between PMCA and calcineurin, suggesting a role for PMCA as a negative modulator of calcineurin-mediated signaling pathways in mammalian cells. This study reinforces the emerging role of PMCA as a molecular organizer and regulator of signaling transduction pathways. [less ▲]

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See detailNovel functional interaction between the plasma membrane Ca2+ pump 4b and the proapoptotic tumor suppressor Ras-associated factor 1 (RASSF1).
Armesilla, Angel L.; Williams, Judith C.; Buch, Mamta H. et al

in The Journal of biological chemistry (2004), 279(30), 31318-28

Plasma membrane calmodulin-dependent calcium ATPases (PMCAs) are enzymatic systems implicated in the extrusion of calcium from the cell. We and others have previously identified molecular interactions ... [more ▼]

Plasma membrane calmodulin-dependent calcium ATPases (PMCAs) are enzymatic systems implicated in the extrusion of calcium from the cell. We and others have previously identified molecular interactions between the cytoplasmic COOH-terminal end of PMCA and PDZ domain-containing proteins. These interactions suggested a new role for PMCA as a modulator of signal transduction pathways. The existence of other intracellular regions in the PMCA molecule prompted us to investigate the possible participation of other domains in interactions with different partner proteins. A two-hybrid screen of a human fetal heart cDNA library, using the region 652-840 of human PMCA4b (located in the catalytic, second intracellular loop) as bait, revealed a novel interaction between PMCA4b and the tumor suppressor RASSF1, a Ras effector protein involved in H-Ras-mediated apoptosis. Immunofluorescence co-localization, immunoprecipitation, and glutathione S-transferase pull-down experiments performed in mammalian cells provided further confirmation of the physical interaction between the two proteins. The interaction domain has been narrowed down to region 74-123 of RASSF1C (144-193 in RASSF1A) and 652-748 of human PMCA4b. The functionality of this interaction was demonstrated by the inhibition of the epidermal growth factor-dependent activation of the Erk pathway when PMCA4b and RASSF1 were co-expressed. This inhibition was abolished by blocking PMCA/RASSSF1 association with an excess of a green fluorescent protein fusion protein containing the region 50-123 of RASSF1C. This work describes a novel protein-protein interaction involving a domain of PMCA other than the COOH terminus. It suggests a function for PMCA4b as an organizer of macromolecular protein complexes, where PMCA4b could recruit diverse proteins through interaction with different domains. Furthermore, the functional association with RASSF1 indicates a role for PMCA4b in the modulation of Ras-mediated signaling. [less ▲]

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See detailPlasma membrane Ca2+ ATPase 4 is required for sperm motility and male fertility.
Schuh, Kai; Cartwright, Elizabeth J.; Jankevics, Eriks et al

in The Journal of biological chemistry (2004), 279(27), 28220-6

Calcium and Ca(2+)-dependent signals play a crucial role in sperm motility and mammalian fertilization, but the molecules and mechanisms underlying these Ca(2+)-dependent pathways are incompletely ... [more ▼]

Calcium and Ca(2+)-dependent signals play a crucial role in sperm motility and mammalian fertilization, but the molecules and mechanisms underlying these Ca(2+)-dependent pathways are incompletely understood. Here we show that homozygous male mice with a targeted gene deletion of isoform 4 of the plasma membrane calcium/calmodulin-dependent calcium ATPase (PMCA), which is highly enriched in the sperm tail, are infertile due to severely impaired sperm motility. Furthermore, the PMCA inhibitor 5-(and-6)-carboxyeosin diacetate succinimidyl ester reduced sperm motility in wild-type animals, thus mimicking the effects of PMCA4 deficiency on sperm motility and supporting the hypothesis of a pivotal role of the PMCA4 on the regulation of sperm function and intracellular Ca(2+) levels. [less ▲]

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