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J. Biol. Chem., Vol. 283, Issue 2, 1128-1136, January 11, 2008

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Regulation of Inositol 1,4,5-Trisphosphate Receptor-mediated Calcium Release by the Na/K-ATPase in Cultured Renal Epithelial Cells^*

Ying Chen, Ting Cai, Changjun Yang, David A. Turner, David R. Giovannucci, and Zijian Xie¹

From the Department of Physiology and Pharmacology and Department of Neuroscience, University of Toledo, College of Medicine, Toledo, Ohio 43614

It is known that the Na/K-ATPase 1 subunit interacts directly with inositol 1,4,5-triphosphate (IP₃) receptors. In this study we tested whether this interaction is required for extracellular stimuli to efficiently regulate endoplasmic reticulum (ER) Ca²⁺ release. Using cultured pig kidney LLC-PK1 cells as a model, we demonstrated that graded knockdown of the cellular Na/K-ATPase 1 subunit resulted in a parallel attenuation of ATP-induced ER Ca²⁺ release. When the knockdown cells were rescued by knocking in a rat 1, the expression of rat 1 restored not only the cellular Na/K-ATPase but also ATP-induced ER Ca²⁺ release. Mechanistically, this defect in ATP-induced ER Ca²⁺ release was neither due to the changes in the amount or the function of cellular IP₃ and P2Y receptors nor the ER Ca²⁺ content. However, the 1 knockdown did redistribute cellular IP₃ receptors. The pool of IP₃ receptors that resided close to the plasma membrane was abolished. Because changes in the plasma membrane proximity could reduce the efficiency of signal transmission from P2Y receptors to the ER, we further determined the dose-dependent effects of ATP on protein kinase C activation and ER Ca²⁺ release. The data showed that the 1 knockdown de-sensitized the ATP-induced ER Ca²⁺ release but not PKC activation. Moreover, expression of the N terminus of Na/K-ATPase 1 subunit not only disrupted the formation of the Na/K-ATPase-IP₃ receptor complex but also abolished the ATP-induced Ca²⁺ release. Finally, we observed that the 1 knockdown was also effective in attenuating ER Ca²⁺ release provoked by angiotensin II and epidermal growth factor.

Received for publication, September 25, 2007 , and in revised form, November 8, 2007.

^* This work was supported by National Institutes of Health Grants HL-36573, HL-67963, and GM-78565 and by American Heart Association Grant 0130231N. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology and Pharmacology, the University of Toledo College of Medicine, 3035 Arlington Ave., Toledo, OH 43614-5804. Tel.: 419-383-4182; Fax: 419-383-2871; E-mail: Zi-Jian.Xie{at}utoledo.edu.

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