Enhancement of calcium signalling dynamics and stability by delayed modulation of the plasma‐membrane calcium‐ATPase in human T cells

Bautista, Diana M.; Hoth, Markus; Lewis, Richard S.

doi:10.1113/jphysiol.2001.016154

Cited by 116 publications

(167 citation statements)

References 56 publications

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“…Mitochondrial Ca 2ϩ uptake can be diminished by treatment with electron transport uncoupling agents oligomycin and antimycin A (24,30). We observed that such inhibition of mitochondrial buffering resulted in a minimal diminution of TCR-mediated peak [Ca 2ϩ ] i in control cells (data not shown) but modestly rescued the blunted maximal [Ca 2ϩ ] i elevation in Vhlh Ϫ/Ϫ cells (Fig.…”

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confidence: 65%

“…Because alterations in TCR proximal signaling, intracellular Ca 2ϩ store content and release, and Ca 2ϩ influx could not explain the effect of Hif-1␣ on Ca 2ϩ signaling in thymocytes, we hypothesized that Hif-1␣ stabilization might increase the rate of removal of Ca 2ϩ from the cytoplasm. PMCA is the major efflux mechanism responsible for recovery of baseline cytoplasmic Ca 2ϩ concentration (24). Total PMCA protein expression appeared similar in control and Vhlh Ϫ/Ϫ thymocytes (Fig.…”

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confidence: 99%

“…This finding was confirmed by measuring PMCAmediated Ca 2ϩ efflux rates. Thymocytes were Ca 2ϩ -loaded for 300 sec, using thapsigargin to block SERCA, deplete ER stores, and produce sustained CRAC-mediated elevation of [Ca 2ϩ ] i , a protocol that fully activates PMCA pumps (24). PMCAdependent Ca 2ϩ i efflux was then measured after a rapid switch to Ca 2ϩ -free bath.…”

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confidence: 99%

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Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Neumann

Yang

Biju

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

106

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Low oxygen pressures exist in many solid tissues, including primary and secondary lymphoid organs. One key element in cellular adaptation to hypoxia is induced expression of hypoxia inducible factor (Hif) 1␣. Here, we have examined the effect of Hif-1␣, isolated from the myriad other effects of hypoxia, on T cell receptor (TCR) signaling in thymocytes. Because pVHL (von Hippel-Lindau protein) directs the proteolysis of Hif-1␣ under ''normoxic'' conditions, we achieved constitutive stabilization of Hif-1␣ through thymic deletion of Vhlh and reversed Hif-1␣ stabilization with double deletion of Vhlh and Hif-1␣. We found that constitutive activity of Hif-1␣ resulted in diminished Ca 2؉ response upon TCR crosslinking despite equivalent activation of phospholipase C␥1, normal intracellular Ca 2؉ stores, and normal entry of Ca 2؉ across the plasma membrane. Altered Ca 2؉ response was instead due to accelerated removal of Ca 2؉ from the cytoplasm into intracellular compartments, which occurred in association with Hif-1␣-dependent overexpression of the calcium pump SERCA2 (sarcoplasmic͞ endoplasmic reticulum calcium ATPase 2). These data suggest a unique mechanism for control of TCR signaling through Hif-1␣, which may be operative at the physiologic oxygen tensions seen in solid lymphoid organs.calcium ͉ lymphocytes

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confidence: 65%

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confidence: 99%

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confidence: 99%

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Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Neumann

Yang

Biju

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

106

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“…The removal of extracellular Ca 2+ after store depletion-induced Ca 2+ influx results in a rapid decline of cytosolic calcium. The rapid decline in cytosolic [Ca 2+ ] could be mediated by Ca 2+ extrusion via SERCA, PMCAs, and uptake by mitochondria (26). When SERCA was inhibited by thapsigargin and mitochondria by antimycin and oligomycin, the cytosolic [Ca 2+ ] decrease in Jurkat cells was mediated almost exclusively by PMCA activity (26).…”

Section: Post Overexpression or Down-regulation Does Not Substantiallymentioning

confidence: 99%

POST, partner of stromal interaction molecule 1 (STIM1), targets STIM1 to multiple transporters

Krapivinsky

Stotz

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

107

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Specialized proteins in the plasma membrane, endoplasmic reticulum (ER), and mitochondria tightly regulate intracellular calcium. A unique mechanism called store-operated calcium entry is activated when ER calcium is depleted, serving to restore intra-ER calcium levels. An ER calcium sensor, stromal interaction molecule 1 (STIM1), translocates within the ER membrane upon store depletion to the juxtaplasma membrane domain, where it interacts with intracellular domains of a highly calcium-selective plasma membrane ion channel, Orai1. STIM1 gates Orai1, allowing calcium to enter the cytoplasm, where it repletes the ER store via calcium-ATPases pumps. Here, we performed affinity purification of Orai1 from Jurkat cells to identify partner of STIM1 (POST), a 10-transmembrane–spanning segment protein of unknown function. The protein is located in the plasma membrane and ER. POST-Orai1 binding is store depletion-independent. On store depletion, the protein binds STIM1 and moves within the ER to localize near the cell membrane. This protein, TMEM20 (POST), does not affect store-operated calcium entry but does reduce plasma membrane Ca 2+ pump activity. Store depletion promotes STIM1–POST complex binding to smooth ER and plasma membrane Ca 2+ ATPases (SERCAs and PMCAs, respectively), Na/K-ATPase, as well as to the nuclear transporters, importins-β and exportins.

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“…Cells were pretreated for 40 min with EGTA (5 mM) or thapsigargin (2 mM), alone or in combination, or pretreated for 2 h with 2 mM Trolox, or treated for 120 h with 1 mg/ml CsA. The graph shows the % of annexin-V þ cells (nX3) p66Shc, mitochondria and Ca 2 þ homeostasis M Pellegrini et al entered through CRAC channels 21 and have been shown to underlie attenuation of Ca 2 þ signaling by the inhibitory coreceptor CD22 in B cells. 22 We therefore investigated the expression levels of PMCA1/4, which are the major T cell species.…”

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p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

et al. 2006

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p66Shc, a redox enzyme that enhances reactive oxygen species (ROS) production by mitochondria, promotes T cell apoptosis. We have addressed the mechanisms regulating p66Shc-dependent apoptosis in T cells exposed to supraphysiological increases in [Ca 2 þ ] c . p66Shc expression resulted in profound mitochondrial dysfunction in response to the Ca 2 þ ionophore A23187, as revealed by dissipation of mitochondrial transmembrane potential, cytochrome c release and decreased ATP levels. p66Shc expression also caused a dramatic alteration in the cells' Ca 2 þ -handling ability, which resulted in Ca 2 þ overload after A23187 treatment. The impairment in Ca 2 þ homeostasis was ROS dependent and caused by defective Ca 2 þ extrusion due at least in part to decreased plasma membrane ATPase (PMCA) expression. Both effects of p66Shc required Ca 2 þ -dependent serine-36 phosphorylation. The mitochondrial effects of p66Shc were potentiated by but not strictly dependent on the rise in [Ca 2 þ ] c . Thus, Ca 2 þ -dependent p66Shc phosphorylation causes both mitochondrial dysfunction and impaired Ca 2 þ homeostasis, which synergize in promoting T cell apoptosis.

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Enhancement of calcium signalling dynamics and stability by delayed modulation of the plasma‐membrane calcium‐ATPase in human T cells

Cited by 116 publications

References 56 publications

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

Hypoxia inducible factor 1α regulates T cell receptor signal transduction

POST, partner of stromal interaction molecule 1 (STIM1), targets STIM1 to multiple transporters

p66SHC promotes T cell apoptosis by inducing mitochondrial dysfunction and impaired Ca2+ homeostasis

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