Department of Physiology, University of Hong Kong, Hong Kong, China.
PLoS One. 2012;7(2):e31905. doi: 10.1371/journal.pone.0031905. Epub 2012 Feb 27.
Intracellular pH (pHi) and Ca(2+) regulate essentially all aspects of cellular activities. Their inter-relationship has not been mechanistically explored. In this study, we used bases and acetic acid to manipulate the pHi. We found that transient pHi rise induced by both organic and inorganic bases, but not acidification induced by acid, produced elevation of cytosolic Ca(2+). The sources of the Ca(2+) increase are from the endoplasmic reticulum (ER) Ca(2+) pools as well as from Ca(2+) influx. The store-mobilization component of the Ca(2+) increase induced by the pHi rise was not sensitive to antagonists for either IP(3)-receptors or ryanodine receptors, but was due to inhibition of the sarco/endoplasmic reticulum Ca(2+)-ATPase (SERCA), leading to depletion of the ER Ca(2+) store. We further showed that the physiological consequence of depletion of the ER Ca(2+) store by pHi rise is the activation of store-operated channels (SOCs) of Orai1 and Stim1, leading to increased Ca(2+) influx. Taken together, our results indicate that intracellular alkalinization inhibits SERCA activity, similar to thapsigargin, thereby resulting in Ca(2+) leak from ER pools followed by Ca(2+) influx via SOCs.
细胞内 pH 值（pHi）和 Ca(2+) 调节着细胞活动的各个方面。它们之间的关系尚未在机制上进行探索。在这项研究中，我们使用碱基和乙酸来操纵 pHi。我们发现，有机碱和无机碱诱导的短暂 pHi 升高会引起细胞溶质 Ca(2+)的升高，但酸化诱导的 pHi 降低不会引起 Ca(2+)的升高。Ca(2+) 升高的来源是内质网（ER）Ca(2+)库以及 Ca(2+)内流。由 pHi 升高引起的 Ca(2+)增加的储存释放成分对 IP(3)-受体或 Ryanodine 受体的拮抗剂均不敏感，但由于抑制肌浆/内质网 Ca(2+)ATP 酶（SERCA），导致 ER Ca(2+)库耗竭。我们进一步表明，pHi 升高导致 ER Ca(2+)库耗竭的生理后果是激活 Orai1 和 Stim1 的储存操作通道（SOCs），导致 Ca(2+)内流增加。总之，我们的结果表明，细胞内碱化抑制 SERCA 活性，类似于 thapsigargin，从而导致 ER 池中的 Ca(2+)泄漏，随后通过 SOCs 进行 Ca(2+)内流。
