Extracellular pH Modifies Mitochondrial Control of Capacitative Calcium Entry in Jurkat Cells

Zabłocki, Krzysztof; Szczepanowska, Joanna; Duszyński, Jerzy

doi:10.1074/jbc.m411507200

Cited by 15 publications

(11 citation statements)

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“…I CRAC in human monocyte-derived macrophages shows an extracellular pH-dependent change of current amplitude with a pK a of 8.2 [40]. Two studies in Jurkat T lymphocytes suggest that extracellular pH modifies the mitochondrial control of SOCE in Jurkat cells [41,42]. Others predict a similar mechanism as assumed for L-type Ca 2+ channels via the protonation of negatively charged glutamate residues close to the channel pore [43,44].…”

Section: Introductionmentioning

confidence: 99%

Regulation of endogenous and heterologous Ca2+ release-activated Ca2+ currents by pH

et al. 2014

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Deviations from physiological pH (~ pH 7.2) as well as altered Ca2+ signaling play important roles in immune disease and cancer. One of the most ubiquitous pathways for cellular Ca2+ influx is the store-operated Ca2+ entry (SOCE) or Ca2+ release-activated Ca2+ current (ICRAC), which is activated upon depletion of intracellular Ca2+ stores. We here show that extracellular and intracellular changes in pH regulate both endogenous ICRAC in Jurkat T lymphocytes and RBL2H3 cells, and heterologous ICRAC in HEK293 cells expressing the molecular components STIM1/2 and Orai1/2/3 (CRACM1/2/3). We find that external acidification suppresses, and alkalization facilitates IP3-induced ICRAC. In the absence of IP3, external alkalization did not elicit endogenous ICRAC but was able to activate heterologous ICRAC in HEK293 cells expressing Orai1/2/3 and STIM1 or STIM2. Similarly, internal acidification reduced IP3-induced activation of endogenous and heterologous ICRAC, while alkalization accelerated its activation kinetics without affecting overall current amplitudes. Mutation of two aspartate residues to uncharged alanine amino acids (D110/112A) in the first extracellular loop of Orai1 significantly attenuated both the inhibition of ICRAC by external acidic pH as well as its facilitation by alkaline conditions. We conclude that intra- and extracellular pH differentially regulates ICRAC. While intracellular pH might affect aggregation and/or binding of STIM to Orai, external pH seems to modulate ICRAC through its channel pore, which in Orai1 is partially mediated by residues D110 and D112.

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Section: Introductionmentioning

confidence: 99%

Regulation of endogenous and heterologous Ca2+ release-activated Ca2+ currents by pH

et al. 2014

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“…The released Ca 2+ from ER or sarcoplasmic reticulum (SR) enters mitochondria and the subsequent rise of mitochondrial Ca 2+ activates several mitochondrial dehydrogenases (Jo et al 2006; Csordas & Hajnoczky, 2009). The mitochondrial Ca 2+ sequestration and/or the mitochondrial metabolites have been reported to fine‐tune the amplitude of SOCE (Hoth et al 1997; Zablocki et al 2005; Parekh, 2008; Schwindling et al 2010). Interestingly, mitochondria accumulate in the vicinity of immunological synapses in Jurkat T cells upon T cell receptor activation (Quintana et al 2007).…”

Section: Introductionmentioning

confidence: 99%

Pivotal role of mitochondrial Na⁺–Ca²⁺ exchange in antigen receptor mediated Ca²⁺ signalling in DT40 and A20 B lymphocytes

Kim

Takeuchi

Koga

et al. 2012

The Journal of Physiology

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“…To fulfill these functions, mitochondria must generate a high electrochemical proton gradient (⌬⌿) across the inner membrane. Their de-energization due to inhibition of the respiratory chain or to uncoupling of oxidative phosphorylation may result in cellular energy deficiency and impairment of ⌬⌿-dependent processes, among them intracellular calcium signaling (11,15,26,27). In metazoa mitochondrial DNA (mtDNA) typically encodes 13 proteins involved in oxidative phosphorylation; two of them are elements of the F o subunit of mitochondrial ATPase, while 11 proteins are components of the respiratory chain complexes I, III, and IV.…”

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Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells

Kozieł

Zabłocki

Duszyński

2006

Antimicrob Agents Chemother

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The effects of ciprofloxacin on mitochondrial DNA (mtDNA) content, oxygen consumption, mitochondrial membrane potential, cellular ATP formation, and capacitative Ca 2؉ entry into Jurkat cells were investigated. In cells incubated for several days with 25 g/ml ciprofloxacin, a 60% reduction of mtDNA content, inhibition of the respiratory chain, and a significant decrease in mitochondrial membrane potential were observed. These changes led to a decrease in the calcium buffering capacity of mitochondria which, in turn, resulted in a gradual inhibition of the capacitative Ca 2؉ entry. On days 4, 7, and 11 of incubation with ciprofloxacin, the initial rates of Ca 2؉ entry were reduced by 33%, 50%, and 50%, respectively. Ciprofloxacin caused a transient decrease in the cellular capability for ATP formation. In cells incubated for 15 min with glucose, pyruvate, and glutamine as exogenous fuel, ciprofloxacin reduced ATP content by 16% and 35% on days 4 and 7, respectively, of incubation with the drug. However, on day 11 of incubation with ciprofloxacin, a recovery of cellular ATP formation was observed. In conclusion, long-term exposure of Jurkat cells to ciprofloxacin at a concentration of 25 g/ml seriously affects cellular energy metabolism and calcium homeostasis.

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Extracellular pH Modifies Mitochondrial Control of Capacitative Calcium Entry in Jurkat Cells

Abstract: It was found that a collapse of the mitochondrial calcium buffering caused by the protonophoric uncoupler CCCP, antimycin A plus oligomycin, or the inhibitor of the mitochondrial Ca 2؉ /Na ؉ exchanger led to a strong inhibition of thapsigargin-induced capacitative Ca

Cited by 15 publications

References 37 publications

Regulation of endogenous and heterologous Ca2+ release-activated Ca2+ currents by pH

Regulation of endogenous and heterologous Ca2+ release-activated Ca2+ currents by pH

Pivotal role of mitochondrial Na⁺–Ca²⁺ exchange in antigen receptor mediated Ca²⁺ signalling in DT40 and A20 B lymphocytes

Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells

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Extracellular pH Modifies Mitochondrial Control of Capacitative Calcium Entry in Jurkat Cells

Abstract: It was found that a collapse of the mitochondrial calcium buffering caused by the protonophoric uncoupler CCCP, antimycin A plus oligomycin, or the inhibitor of the mitochondrial Ca 2؉ /Na ؉ exchanger led to a strong inhibition of thapsigargin-induced capacitative Ca

Cited by 15 publications

References 37 publications

Regulation of endogenous and heterologous Ca2+ release-activated Ca2+ currents by pH

Regulation of endogenous and heterologous Ca2+ release-activated Ca2+ currents by pH

Pivotal role of mitochondrial Na+–Ca2+ exchange in antigen receptor mediated Ca2+ signalling in DT40 and A20 B lymphocytes

Calcium Signals Are Affected by Ciprofloxacin as a Consequence of Reduction of Mitochondrial DNA Content in Jurkat Cells

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Pivotal role of mitochondrial Na⁺–Ca²⁺ exchange in antigen receptor mediated Ca²⁺ signalling in DT40 and A20 B lymphocytes