The Experts below are selected from a list of 237 Experts worldwide ranked by ideXlab platform
Howard S. Young - One of the best experts on this subject based on the ideXlab platform.
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sarcolambans are phospholamban and sarcolipin like regulators of the sarcoplasmic reticulum Calcium Pump serca
bioRxiv, 2020Co-Authors: Jessi J Bak, Seth L. Robia, Rodrigo Aguayoortiz, Muhammad Bashir Khan, Joanne M Lemieux, Lennane Michel Espinozafonseca, Howard S. YoungAbstract:ABSTRACT From insects to humans, Calcium signaling is essential for life. An important part of this process is the sarco-endoplasmic reticulum Calcium Pump SERCA, which maintains low cytosolic Calcium levels required for intracellular Calcium homeostasis. In higher organisms, this is a tightly controlled system where SERCA interacts with tissuespecific regulatory subunits such as phospholamban in cardiac muscle and sarcolipin in skeletal muscle. With the recent discovery of the sarcolambans, the family of Calcium Pump regulatory subunits also appears to be ancient, spanning more than 550 million years of evolutionary divergence from insects to humans. This evolutionary divergence is reflected in the peptide sequences, which vary enormously from one another and range from vaguely phospholamban-like to vaguely sarcolipin-like. Here, our goal was to investigate select sarcolamban peptides for their ability to regulate Calcium Pump activity. For a side-by-side comparison of diverse sarcolamban peptides, we tested them against mammalian skeletal muscle SERCA1a. This allowed us to determine if the sarcolamban peptides mimic phospholamban and sarcolipin in their regulatory activities. Four sarcolamban peptides were chosen from different invertebrate species. Of these, we were able to express and purify sarcolamban peptides from bumble bee, water flea, and tadpole shrimp. Sarcolamban peptides were co-reconstituted into proteoliposomes with mammalian SERCA1a and the effect of each peptide on the apparent Calcium affinity and maximal activity of SERCA was measured. While all peptides were super-inhibitors of SERCA, they exhibited either phospholamban-like or sarcolipin-like characteristics. Molecular modeling, protein-protein docking, and molecular dynamics simulations were used to reveal novel features of insect versus mammalian Calcium Pumps and the sarcolamban regulatory subunits.
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The phospholamban pentamer interacts with the sarcoplasmic reticulum Calcium Pump SERCA
2018Co-Authors: Howard S. Young, John Paul Glaves, Joseph O. Primeau, M. Joanne Lemieux, L. Michel Espinoza-fonsecaAbstract:The interaction of phospholamban with the sarcoplasmic reticulum Calcium Pump (SERCA) is a major regulatory axis in cardiac muscle contractility. The prevailing model involves reversible inhibition of SERCA by monomeric phospholamban and storage of phospholamban as an inactive pentamer. However, this paradigm has been challenged by studies demonstrating that phospholamban remains associated with SERCA and that the phospholamban pentamer is required for cardiac contractility. We have previously used two-dimensional crystallization and electron microscopy to study the interaction between SERCA and phospholamban. To further understand this interaction, we compared small helical crystals and large two-dimensional crystals of SERCA in the absence and presence of phospholamban. In both crystal forms, SERCA molecules are organized into identical anti-parallel dimer ribbons. The dimer ribbons pack together with distinct crystal contacts in the helical versus large two-dimensional crystals, which allow phospholamban differential access to potential sites of interaction with SERCA. Nonetheless, we show that a phospholamban oligomer interacts with SERCA in a similar manner in both crystal forms. In the two-dimensional crystals, a phospholamban pentamer interacts with transmembrane segments M3 of SERCA and participates in a crystal contact that bridges neighboring SERCA dimer ribbons. In the helical crystals, an oligomeric form of phospholamban also interacts with M3 of SERCA, though the phospholamban oligomer straddles a SERCA-SERCA crystal contact. We conclude that the pentameric form of phospholamban interacts with SERCA, and that it plays distinct structural and functional roles in SERCA regulation.
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Skin cells prefer a slower Calcium Pump.
The Journal of biological chemistry, 2018Co-Authors: Seth L. Robia, Howard S. YoungAbstract:Naturally occurring mutations of a Calcium ion transporter can cause a skin condition known as Darier's disease. In this issue of JBC, Mikkelsen et al. describe a particularly interesting Darier's mutation that alters Calcium transport by disrupting a kinetic braking mechanism that is unique to the SERCA2b Calcium Pump isoform. The study provides new insight into the intrinsic regulation of this transporter and reveals how disruption of regulation can lead to disease in Darier's patients.
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the molecular basis for cyclopiazonic acid inhibition of the sarcoplasmic reticulum Calcium Pump
Journal of Biological Chemistry, 2007Co-Authors: Karine Moncoq, Catharine A Trieber, Howard S. YoungAbstract:Abstract The sarcoplasmic reticulum Ca2+-ATPase is essential for Calcium reuptake in the muscle contraction-relaxation cycle. Here we present structures of a Calcium-free state with bound cyclopiazonic acid (CPA) and magnesium fluoride at 2.65A resolution and a Calcium-free state with bound CPA and ADP at 3.4A resolution. In both structures, CPA occupies the Calcium access channel delimited by transmembrane segments M1–M4. Inhibition of Ca2+-ATPase is stabilized by a polar pocket that surrounds the tetramic acid of CPA and a hydrophobic platform that cradles the inhibitor. The Calcium Pump residues involved include Gln56, Leu61, Val62, and Asn101. We conclude that CPA inhibits the Calcium Pump by blocking the Calcium access channel and immobilizing a subset of transmembrane helices. In the E2(CPA) structure, ADP is bound in a distinct orientation within the nucleotide binding pocket. The adenine ring is sandwiched between Arg489 of the nucleotide-binding domain and Arg678 of the phosphorylation domain. This mode of binding conforms to an adenine recognition motif commonly found in ATP-dependent proteins.
Ludwig Neyses - One of the best experts on this subject based on the ideXlab platform.
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Targeting the sarcolemmal Calcium Pump: A potential novel strategy for the treatment of cardiovascular disease
Cardiovascular & hematological agents in medicinal chemistry, 2007Co-Authors: Delvac Oceandy, Mamas A. Mamas, Ludwig NeysesAbstract: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.
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Calcium transport in cardiovascular health and disease-the sarcolemmal Calcium Pump enters the stage. Invited Review
Journal of Molecular and Cellular Cardiology, 2005Co-Authors: Elizabeth J. Cartwright, Kai Schuh, Ludwig NeysesAbstract:Calcium is known to be one of the most important ionic regulators of the heart, where it has a crucial role in contraction-relaxation. Within a single beat of the cardiomyocyte there is a 100-fold increase in the cytosolic free Ca(2+) level, this must be returned to its original concentration in order to maintain the normal physiological function of the cell. Two of the mechanisms involved in returning the Ca(2+) concentration back to resting levels are located at the sarcolemma; the sodium/Calcium exchanger (NCX) and the sarcolemmal Calcium Pump. Compared to the NCX the sarcolemmal Calcium Pump extrudes significantly less Calcium from the cardiomyocyte and has long been thought to be involved in the maintenance of low diastolic Calcium levels. This review will outline recent evidence suggesting that the sarcolemmal Calcium Pump may in fact play a key role in signal transduction in the cardiovascular system.
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Calcium transport in cardiovascular health and disease--the sarcolemmal Calcium Pump enters the stage.
Journal of molecular and cellular cardiology, 2005Co-Authors: Elizabeth J. Cartwright, Kai Schuh, Ludwig NeysesAbstract:Calcium is known to be one of the most important ionic regulators of the heart, where it has a crucial role in contraction–relaxation. Within a single beat of the cardiomyocyte there is a 100-fold increase in the cytosolic free Ca2+ level, this must be returned to its original concentration in order to maintain the normal physiological function of the cell. Two of the mechanisms involved in returning the Ca2+ concentration back to resting levels are located at the sarcolemma; the sodium/Calcium exchanger (NCX) and the sarcolemmal Calcium Pump. Compared to the NCX the sarcolemmal Calcium Pump extrudes significantly less Calcium from the cardiomyocyte and has long been thought to be involved in the maintenance of low diastolic Calcium levels. This review will outline recent evidence suggesting that the sarcolemmal Calcium Pump may in fact play a key role in signal transduction in the cardiovascular system.
Elizabeth J. Cartwright - One of the best experts on this subject based on the ideXlab platform.
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Abstract 3847: Cardiac Contractility is Differentially Modulated by Isoforms 1 and 4 of the Plasma Membrane Calcium Pump
Circulation, 2009Co-Authors: Mohamed A. Shaheen, Delvac Oceandy, Tamer M.a. Mohamed, Sukhpal Prehar, Nasser Alatwi, Zeinab Hegab, Florence Baudoin, Michael Emerson, Elizabeth J. CartwrightAbstract:Ca2+ plays a crucial role in excitation-contraction coupling as well as in cardiac signal transduction. Two isoforms of the plasma membrane Calcium Pump (PMCA), PMCA1 and 4, are expressed in the my...
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Calcium transport in cardiovascular health and disease-the sarcolemmal Calcium Pump enters the stage. Invited Review
Journal of Molecular and Cellular Cardiology, 2005Co-Authors: Elizabeth J. Cartwright, Kai Schuh, Ludwig NeysesAbstract:Calcium is known to be one of the most important ionic regulators of the heart, where it has a crucial role in contraction-relaxation. Within a single beat of the cardiomyocyte there is a 100-fold increase in the cytosolic free Ca(2+) level, this must be returned to its original concentration in order to maintain the normal physiological function of the cell. Two of the mechanisms involved in returning the Ca(2+) concentration back to resting levels are located at the sarcolemma; the sodium/Calcium exchanger (NCX) and the sarcolemmal Calcium Pump. Compared to the NCX the sarcolemmal Calcium Pump extrudes significantly less Calcium from the cardiomyocyte and has long been thought to be involved in the maintenance of low diastolic Calcium levels. This review will outline recent evidence suggesting that the sarcolemmal Calcium Pump may in fact play a key role in signal transduction in the cardiovascular system.
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Calcium transport in cardiovascular health and disease--the sarcolemmal Calcium Pump enters the stage.
Journal of molecular and cellular cardiology, 2005Co-Authors: Elizabeth J. Cartwright, Kai Schuh, Ludwig NeysesAbstract:Calcium is known to be one of the most important ionic regulators of the heart, where it has a crucial role in contraction–relaxation. Within a single beat of the cardiomyocyte there is a 100-fold increase in the cytosolic free Ca2+ level, this must be returned to its original concentration in order to maintain the normal physiological function of the cell. Two of the mechanisms involved in returning the Ca2+ concentration back to resting levels are located at the sarcolemma; the sodium/Calcium exchanger (NCX) and the sarcolemmal Calcium Pump. Compared to the NCX the sarcolemmal Calcium Pump extrudes significantly less Calcium from the cardiomyocyte and has long been thought to be involved in the maintenance of low diastolic Calcium levels. This review will outline recent evidence suggesting that the sarcolemmal Calcium Pump may in fact play a key role in signal transduction in the cardiovascular system.
Béla Papp - One of the best experts on this subject based on the ideXlab platform.
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Loss of endoplasmic reticulum Calcium Pump expression in choroid plexus tumours.
Neuropathology and applied neurobiology, 2014Co-Authors: Lamia Ait-ghezali, Atousa Arbabian, Astrid Jeibmann, Martin Hasselblatt, Giorgio Hallaert, Caroline Van Den Broecke, Françoise Gray, Jean-philippe Brouland, Nadine Varin-blank, Béla PappAbstract:Aims Sarco/Endoplasmic Reticulum Calcium ATPase-type Calcium Pumps (SERCA enzymes) control cell activation by sequestering Calcium ions from the cytosol into the endoplasmic reticulum. Although endoplasmic reticulum Calcium signalling plays an important role in the regulation of choroid plexus epithelial function, SERCA expression in the choroid plexus has not been investigated so far. Methods In this work we investigated the expression of the SERCA3-type Calcium Pump in choroid plexus epithelial cells grown in vitro, and in normal and hyperplastic choroid plexus tissue, in choroid plexus papillomas displaying various degrees of atypia, and in choroid plexus carcinoma by immunohistochemistry in situ. Results Whereas normal choroid plexus epithelial cells express SERCA3 abundantly, SERCA3 expression is strongly decreased in papillomas, and is absent in choroid plexus carcinoma, while expression in hyperplastic epithelium is high, similarly to normal epithelium. SERCA3 expression was detected also in normal primary choroid plexus epithelial cells grown in vitro, and expression was markedly enhanced by short-chain fatty acid-type cell differentiation inducing agents, including valproate. Conclusion These observations show that SERCA3 is a new phenotypic marker of normal choroid plexus epithelial differentiation, and that SERCA3 constitutes an early tumour marker ‘by loss of expression’ in the choroid plexus that may be useful to distinguish hyperplastic processes from papillomas. Endoplasmic reticulum Calcium homeostasis becomes anomalous, due to loss of SERCA3 expression, already in benign neoplastic lesions of the choroid plexus epithelium.
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Modulation of endoplasmic reticulum Calcium Pump expression during T lymphocyte activation.
The Journal of biological chemistry, 1997Co-Authors: Sophie Launay, Tünde Kovács, Jocelyne Enouf, Regis Bobe, Christine Lacabaratz-porret, Raymonde Bredoux, Béla PappAbstract:Abstract Calcium mobilization from intracellular storage organelles is a key component of the second messenger system inducing cell activation. Calcium transport ATPases associated with intracellular Calcium storage organelles play a major role in controlling this process by accumulating Calcium from the cytosol into intracellular Calcium pools. In this study the modulation of the expression of the sarco-endoplasmic reticulum Calcium transport ATPase (SERCA) isoenzymes has been studied in lymphocytes undergoing phorbol myristate acetate and ionomycin-induced activation. In several T lymphocyte cell lines a combined treatment by the two drugs resulted in an approximately 90% decrease of the expression of the Calcium Pump isoform recognized by the PLIM430 isoform-specific antibody, whereas the expression of the SERCA 2b isoform was increased approximately 2-fold. Phorbol ester or ionomycin applied separately was ineffective. In Jurkat T cells the down-modulation of expression of the SERCA isoform recognized by the PLIM430 antibody appeared concomitantly with the induction of interleukin-2 expression and could be inhibited by the immunosuppressant drug cyclosporine-A. These data indicate that T cell activation induces a selective and cyclosporine-A-sensitive modulation of the expression of the SERCA Calcium Pump isoforms. This reflects a profound reorganization of the Calcium homeostasis of T cells undergoing activation and may open new avenues in the understanding of the plasticity of the Calcium homeostasis of differentiating cells and in the pharmacological modulation of lymphocyte function.
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Characterization of the inositol trisphosphate-sensitive and insensitive Calcium stores by selective inhibition of the endoplasmic reticulum-type Calcium Pump isoforms in isolated platelet membrane vesicles.
Cell calcium, 1993Co-Authors: Béla Papp, Balázs Sarkadi, G. Gárdos, Katalin Pászty, Tünde Kovács, Jocelyne Enouf, Ágnes EnyediAbstract:In mixed platelet membrane vesicles the presence of two distinct endoplasmic reticulum-type Calcium Pump enzymes of 100 and 97 kD molecular mass has been demonstrated. We have previously shown that both Calcium Pumps were recognized by polyclonal anti-sarcoplasmic reticulum Calcium Pump antisera [11]. In the present work we studied the effects of several Calcium Pump inhibitors on active Calcium transport and inositol trisphosphate-induced Calcium release in these vesicles in an attempt to assign the two Calcium Pump isoenzymes to specific Calcium pools. The effect of the PLIM 430 inhibitory anti-Calcium Pump antibody was compared to that of other Calcium Pump inhibitors acting predominantly on the 100 and the 97 kD Calcium Pump isoforms, respectively. The PLIM 430 antibody, which recognized the 97 kD Pump on Western blots and 2,5-di-(tert-butyl)-1,4-benzohydroquinone, which inhibited phosphoenzyme formation of the same Pump isoform, inhibited Calcium accumulation predominantly into an inositol trisphosphate-releasable Calcium pool. On the other hand, low concentration of thapsigargin, which inhibited phosphoenzyme formation mainly of the 100 kD Pump isozyme, had a more pronounced effect on Calcium uptake into an inositol trisphosphate-resistant pool. These data suggest that in platelets the 97 kD Calcium Pump isoform is likely to be associated with the inositol trisphosphate-sensitive Calcium storage organelle.
Kai Schuh - One of the best experts on this subject based on the ideXlab platform.
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Calcium transport in cardiovascular health and disease-the sarcolemmal Calcium Pump enters the stage. Invited Review
Journal of Molecular and Cellular Cardiology, 2005Co-Authors: Elizabeth J. Cartwright, Kai Schuh, Ludwig NeysesAbstract:Calcium is known to be one of the most important ionic regulators of the heart, where it has a crucial role in contraction-relaxation. Within a single beat of the cardiomyocyte there is a 100-fold increase in the cytosolic free Ca(2+) level, this must be returned to its original concentration in order to maintain the normal physiological function of the cell. Two of the mechanisms involved in returning the Ca(2+) concentration back to resting levels are located at the sarcolemma; the sodium/Calcium exchanger (NCX) and the sarcolemmal Calcium Pump. Compared to the NCX the sarcolemmal Calcium Pump extrudes significantly less Calcium from the cardiomyocyte and has long been thought to be involved in the maintenance of low diastolic Calcium levels. This review will outline recent evidence suggesting that the sarcolemmal Calcium Pump may in fact play a key role in signal transduction in the cardiovascular system.
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Calcium transport in cardiovascular health and disease--the sarcolemmal Calcium Pump enters the stage.
Journal of molecular and cellular cardiology, 2005Co-Authors: Elizabeth J. Cartwright, Kai Schuh, Ludwig NeysesAbstract:Calcium is known to be one of the most important ionic regulators of the heart, where it has a crucial role in contraction–relaxation. Within a single beat of the cardiomyocyte there is a 100-fold increase in the cytosolic free Ca2+ level, this must be returned to its original concentration in order to maintain the normal physiological function of the cell. Two of the mechanisms involved in returning the Ca2+ concentration back to resting levels are located at the sarcolemma; the sodium/Calcium exchanger (NCX) and the sarcolemmal Calcium Pump. Compared to the NCX the sarcolemmal Calcium Pump extrudes significantly less Calcium from the cardiomyocyte and has long been thought to be involved in the maintenance of low diastolic Calcium levels. This review will outline recent evidence suggesting that the sarcolemmal Calcium Pump may in fact play a key role in signal transduction in the cardiovascular system.
