Ariel J. Caride
Mayo Clinic
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Publication
Featured researches published by Ariel J. Caride.
Annals of the New York Academy of Sciences | 2007
Emanuel E. Strehler; Ariel J. Caride; Adelaida G. Filoteo; Yuning Xiong; John T. Penniston; Ágnes Enyedi
Abstract: Plasma membrane Ca2+ ATPases (PMCAs) are essential components of the cellular toolkit to regulate and fine‐tune cytosolic Ca2+ concentrations. Historically, the PMCAs have been assigned a housekeeping role in the maintenance of intracellular Ca2+ homeostasis. More recent work has revealed a perplexing multitude of PMCA isoforms and alternative splice variants, raising questions about their specific role in Ca2+ handling under conditions of varying Ca2+ loads. Studies on the kinetics of individual isoforms, combined with expression and localization studies suggest that PMCAs are optimized to function in Ca2+ regulation according to tissue‐ and cell‐specific demands. Different PMCA isoforms help control slow, tonic Ca2+ signals in some cells and rapid, efficient Ca2+ extrusion in others. Localized Ca2+ handling requires targeting of the pumps to specialized cellular locales, such as the apical membrane of cochlear hair cells or the basolateral membrane of kidney epithelial cells. Recent studies suggest that alternatively spliced regions in the PMCAs are responsible for their unique targeting, membrane localization, and signaling cross‐talk. The regulated deployment and retrieval of PMCAs from specific membranes provide a dynamic system for a cell to respond to changing needs of Ca2+ regulation.
Biochemical Society Transactions | 2007
Emanuel E. Strehler; Adelaida G. Filoteo; John T. Penniston; Ariel J. Caride
Plasma-membrane calcium pumps [PMCAs (plasma-membrane Ca(2+)-ATPases)] expel Ca(2+) from eukaryotic cells to maintain overall Ca(2+) homoeostasis and to provide local control of intracellular Ca(2+) signalling. Recent work indicates functional versatility among PMCA isoforms, with specific pumps being essential for cochlear hair cell function, sperm motility, feedback signalling in the heart and pre- and post-synaptic Ca(2+) regulation in neurons. The functional versatility of PMCAs is due to differences in their regulation by CaM (calmodulin), kinases and other signalling proteins, as well as to their differential targeting and retention in defined plasma membrane domains. The basis for this is the structural diversity of PMCAs. In mammals, four genes encode PMCA isoforms 1-4, and each of these has multiple variants generated by alternative RNA splicing. The alternatively spliced regions are intimately involved in the regulatory interactions and differential membrane localization of the pumps. The alternatively spliced C-terminal tail acts as an autoinhibitory domain by interacting with the catalytic core of the pump. The degree of inhibition and the kinetics of interaction with the major activator CaM differ between PMCA variants. This translates into functional differences in how PMCAs handle Ca(2+) signals of different magnitude and frequency. Accumulating evidence thus demonstrates how structural diversity provides functional versatility in the PMCAs.
Journal of Biological Chemistry | 2003
Raúl A. Marinelli; Pamela S. Tietz; Ariel J. Caride; Bing Q. Huang; Nicholas F. LaRusso
Previous work from our laboratory supports an important role for aquaporins (AQPs), a family of water channel proteins, in bile secretion by hepatocytes. To further define the pathways and molecular mechanisms for water movement across hepatocytes, we directly assessed osmotic water permeability (Pf) and activation energy (Ea) in highly purified, rat hepatocytes basolateral membrane vesicles (BLMV) and canalicular membrane (CMV) vesicles by measuring scattered light intensity using stopped-flow spectrophotometry. The time course of scattered light for BLMV and CMV fit well to a single-exponential function. In BLMV, Pf was 108 ± 4 μm·s–1 (25 °C) with an Ea of 7.7 kcal/mol; in CMV, Pf was 86 ± 5 μm·s–1 (25 °C) with an Ea of 8.0 kcal/mol. The AQP blocker, dimethyl sulfoxide, significantly inhibited the Pf of both basolateral (81 ± 4 μm·s–1; –25%) and canalicular (59 ± 4 μm·s–1; –30%) membrane vesicles. When CMV were isolated from hepatocytes treated with dibutyryl cAMP, a double-exponential fit was needed, implying two functionally different vesicle populations; one population had Pf and Ea values similar to those of CMV from untreated hepatocytes, but the other population had a very high Pf (655 ± 135 μm·s–1, 25 °C) and very low Ea (2.8 kcal/mol). Dimethyl sulfoxide completely inhibited the high Pf value in this second vesicle population. In contrast, Pf and Ea of BLMV were unaltered by cAMP treatment of hepatocytes. Our results are consistent with the presence of both lipid- and AQP-mediated pathways for basolateral and canalicular water movement across the hepatocyte plasma membrane barrier. Our data also suggest that the hepatocyte canalicular membrane domain is rate-limiting for transcellular water transport and that this domain becomes more permeable to water when hepatocytes are exposed to a choleretic agonist, presumably by insertion of AQP molecules. These data suggest a molecular mechanism for the efficient coupling of osmotically active solutes and water transport during canalicular bile formation.
American Journal of Physiology-cell Physiology | 1989
James L. Borke; Ariel J. Caride; Anil K. Verma; Lucky K. Kelley; Carl H. Smith; John T. Penniston; Rajiv Kumar
The syncytiotrophoblast represents the primary cellular barrier between maternal and fetal circulations in the placenta. Large amounts of Ca2+ are transported across this barrier by mechanisms that are not clearly understood. To further understand this phenomenon, we examined rat and human placenta by immunohistochemical and protein blotting techniques with a monoclonal antibody raised against the human erythrocyte plasma membrane Ca2+ pump. Immunohistochemistry with this antibody showed specific staining in the human placenta of the basal (fetal facing) surface of the syncytiotrophoblast. In the rat placenta, immunohistochemistry also showed specific staining of the innermost (fetal facing) layer of the trophoblast and the basal surface of the endoderm of the intraplacental yolk sac. In Western blots of placental homogenates and membranes, the monoclonal antibody bound to a 140,000-mol wt band, characteristic of Ca2+ pumps in other tissues. Western blots of isolated basal membranes showed more intense staining than isolated microvillous membranes, confirming the results of the immunohistochemistry. In addition, Ca2+ transport in basal membrane vesicles from human placenta was inhibited by polyclonal antibodies prepared against the erythrocyte Ca2+ pump. We conclude that basal (fetal facing) layers of human and rat placentas contain a high-affinity Ca2+ pump situated to transport Ca2+ from the maternal to the fetal circulation.
Brain Research | 1989
James L. Borke; Ariel J. Caride; Tony L. Yaksh; John T. Penniston; Rajiv Kumar
A major unanswered question in central nervous system physiology concerns the mechanism by which cerebrospinal fluid (CSF) Ca2+ homeostasis is maintained in the face of hypo- or hypercalcemia. To address this question, we sought and found a protein of Mr approximately 140,000 in choroid plexus plasma membranes that forms a phosphorylated intermediate with characteristics of a plasma membrane Ca2+-pump. A choroid plexus plasma membrane protein of this molecular weight also bound to a monoclonal antibody prepared against the human erythrocyte plasma membrane Ca2+-Mg2+ ATPase Ca2+-pump. When this monoclonal antibody was used for immunohistochemical localization, the plasma membrane Ca2+-pump was found primarily in the CSF-facing membranes of choroid plexus cells from rats, cats, and man. The localization of a plasma membrane Ca2+-pump in the CSF-facing membranes of the choroid plexus suggests that the choroid plexus, by mechanisms including this pump, may regulate CSF Ca2+ concentrations.
Pflügers Archiv: European Journal of Physiology | 1990
James L. Borke; Ariel J. Caride; Anil K. Verma; John T. Penniston; Rajiv Kumar
We used a monoclonal antibody (5F10) specific for the human erythrocyte plasma membrane Ca++-pump to demonstrate the presence and distribution of Ca++-pump epitopes in rat intestine. In paraffin embedded tissue sections, antibody 5F10 binds to epitopes in the basolateral membranes of absorptive cells in rat duodenum and portions of jejunum but not ileum. Western blot analysis of intestinal mucosal proteins with antibody 5F10 shows binding of antibody to major bands of Mr ≈ 135,000 and Mr ≈ 72,000, and to lesser bands of Mr ≈ 125,000 and Mr ≈ 27,000. This pattern was seen in mucosal homogenates of rat duodenal and jejunal cells and to a lesser extent in ileal cells. The Mr ≈ 135,000 band corresponds to the molecular weight of Ca++-pumps in other tissues. The other bands correspond in size to known proteolytic fragments of the Ca++-pump. Slot-blot analysis of nitrocellulose immobilized mucosal homogenates shows binding of 5F10 to be greatest in duodenum and least in ileum. Ca++- transport studies by the everted gut sac technique show a correlation between vitamin D induction of active Ca++-transport and the segmental distribution of Ca++-pump epitopes.
Journal of Biological Chemistry | 2007
Ariel J. Caride; Adelaida G. Filoteo; John T. Penniston; Emanuel E. Strehler
The inhibition by the regulatory domain and the interaction with calmodulin (CaM) vary among plasma membrane calcium pump (PMCA) isoforms. To explore these differences, the kinetics of CaM effects on PMCA4a were investigated and compared with those of PMCA4b. The maximal apparent rate constant for CaM activation of PMCA4a was almost twice that for PMCA4b, whereas the rates of activation for both isoforms showed similar dependence on Ca2+. The inactivation of PMCA4a by CaM removal was also faster than for PMCA4b, and Ca2+ showed a much smaller effect (2- versus 30-fold modification). The rate constants of the individual steps that determine the overall rates were obtained from stopped-flow experiments in which binding of TA-CaM was observed by changes in its fluorescence. TA-CaM binds to two conformations of PMCA4a, an “open” conformation with high activity, and a “closed” one with lower activity. Compared with PMCA4b (Penheiter, A. R., Bajzer, Z., Filoteo, A. G., Thorogate, R., Török, K., and Caride, A. J. (2003) Biochemistry 41, 12115–12124), the model for PMCA4a predicts less inhibition in the closed form and a much faster equilibrium between the open and closed forms. Based on the available kinetic parameters, we determined the constants to fit the shape of a Ca2+ signal in PMCA4b-overexpressing Chinese hamster ovary cells. Using the constants for PMCA4a, and allowing small variations in parameters of other systems contributing to a Ca2+ signal, we then simulated the effect of PMCA4a on the shape of a Ca2+ signal in Chinese hamster ovary cells. The results reproduce the published data (Brini, M., Coletto, L., Pierobon, N., Kraev, N., Guerini, D., and Carafoli, E. (2003) J. Biol. Chem. 278, 24500–24508), and thereby demonstrate the importance of altered regulatory kinetics for the different functional properties of PMCA isoforms.
Genes, Chromosomes and Cancer | 2013
Andrew L. Feldman; George Vasmatzis; Yan W. Asmann; Jaime Davila; Sumit Middha; Bruce W. Eckloff; Sarah H. Johnson; Julie C. Porcher; Stephen M. Ansell; Ariel J. Caride
Chromosomal translocations leading to expression of abnormal fusion proteins play a major role in the pathogenesis of various hematologic malignancies. The recent development of high‐throughput, “deep” sequencing has allowed discovery of novel translocations leading to a rapid increase in understanding these diseases. Translocations involving the anaplastic lymphoma kinase (ALK) gene leading to ALK fusion proteins originally were discovered in anaplastic large cell lymphomas (ALCLs). Among ALCLs, NPM1‐ALK fusions are most common and lead to nuclear localization of the fusion protein. Here, we present a 50‐year‐old male with ALCL demonstrating cytoplasmic ALK immunoreactivity only, suggesting the presence of a non‐NPM1 fusion partner. We performed deep RNA sequencing of tumor tissue from this patient and identified a novel transcript fusing Exon 6 of TRAF1 to Exon 20 of ALK. The TRAF1‐ALK fusion transcript was confirmed at the mRNA level by Sanger sequencing and the fusion protein was visualized by Western blot. The discovery of this TRAF1‐ALK fusion expands the diversity of known ALK fusion partners and highlights the power of deep sequencing for fusion transcript discovery.
Journal of Laboratory and Clinical Medicine | 1998
Ariel J. Caride; Eduardo N. Chini; Sumiko Homma; John T. Penniston; Thomas P. Dousa
To survey the presence of the four different isoforms of the plasma membrane calcium pump (PMCA) and their alternative splicing variants in the rat kidney, three major zones (cortex, outer medulla, and inner medulla) were macrodissected and probed for the presence of mRNA encoding these isoforms and their variants at the splicing site C by using reverse transcription-polymerase chain reaction (RT-PCR). Both the cortex and the outer medulla showed PMCA 1b, 2b, 3(a and c), and 4b. Semiquantitative comparisons indicated that isoform 2b is more abundant in the cortex than in the outer medulla and conversely, that isoform 3 (a and c) is more abundant in the outer medulla than in the cortex. The inner medulla showed only mRNA for isoforms 1b and 4b. The nephron segments present in the cortex and outer medulla were microdissected and analyzed by RT-PCR. Isoforms 1b, 2b, and 4b were found in all nephron segments but were found more frequently in tubular segments with high rates of Ca2+ reabsorption, suggesting that these isoforms may be involved in transepithelial transport. On the other hand, mRNA encoding isoform 3 (a and c) was most abundant in descending thin limb of Henle but was detected also in glomeruli and cortical thin ascending limb. Its distinct localization suggests that this isoform might have another function, such as in intracellular signalling.
Science Signaling | 2015
Katalin Pászty; Ariel J. Caride; Željko Bajzer; Chetan P. Offord; Rita Padányi; Luca Hegedus; Karolina Varga; Emanuel E. Strehler; Ágnes Enyedi
Plasma membrane calcium pumps differentially affect the pattern of calcium signals. Shaping the calcium signal Cells use spatially and locally controlled calcium signals to regulate specific responses and have multiple mechanisms for regulating cytosolic calcium and for removing cytosolic calcium after stimuli that trigger its increase. Pászty et al. investigated how the Ca2+-ATPases that pump calcium out of the cell (PMCAs) contribute to the shape of calcium signals under conditions in which the internal calcium stores have been depleted and cannot contribute to clearing of the calcium from the cytosol. The pattern of calcium signals (oscillating, sustained elevation, or rapid return to baseline) produced in multiple cultured cell lines depended on the abundance of the specific PMCA isoforms, which have different kinetic and regulatory properties. The authors developed a mathematical model that recapitulated the calcium signaling patterns observed in the cultured cells and used the model to identify which properties of PMCA were critical for producing an oscillating Ca2+ pattern. Calcium (Ca2+) is a critical cofactor and signaling mediator in cells, and the concentration of cytosolic Ca2+ is regulated by multiple proteins, including the plasma membrane Ca2+–ATPases (adenosine triphosphatases) (PMCAs), which use ATP to transport Ca2+ out of cells. PMCA isoforms exhibit different kinetic and regulatory properties; thus, the presence and relative abundance of individual isoforms may help shape Ca2+ transients and cellular responses. We studied the effects of three PMCA isoforms (PMCA4a, PMCA4b, and PMCA2b) on Ca2+ transients elicited by conditions that trigger store-operated Ca2+ entry (SOCE) and that blocked Ca2+ uptake into the endoplasmic reticulum in HeLa cells, human embryonic kidney (HEK) 293 cells, or primary endothelial cell isolated from human umbilical cord veins (HUVECs). The slowly activating PMCA4b isoform produced long-lasting Ca2+ oscillations in response to SOCE. The fast-activating isoforms PMCA2b and PMCA4a produced different effects. PMCA2b resulted in rapid and highly PMCA abundance–sensitive clearance of SOCE-mediated Ca2+ transients, whereas PMCA4a reduced cytosolic Ca2+, resulting in the establishment of a higher than baseline cytosolic Ca2+ concentration. Mathematical modeling showed that slow activation was critical to the sustained oscillation induced by the “slow” PMCA4b pump. The modeling and experimental results indicated that the distinct properties of PMCA isoforms differentially regulate the pattern of SOCE-mediated Ca2+ transients, which would thus affect the activation of downstream signaling pathways.