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J. Biol. Chem., Vol. 279, Issue 37, 38495-38502, September 10, 2004

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The Ca²⁺ Homeostasis Defects in a pgm2 Strain of Saccharomyces cerevisiae Are Caused by Excessive Vacuolar Ca²⁺ Uptake Mediated by the Ca²⁺-ATPase Pmc1p^*

David P. Aiello, Lianwu Fu, Attila Miseta¶, Katalin Sipos||, and David M. Bedwell**

From the Department of Microbiology, University of Alabama at Birmingham, Birmingham, Alabama, and Departments of ^¶Clinical Chemistry and ^||Biochemistry, University Medical School, Peçs H-7624, Hungary

Loss of the major isoform of phosphoglucomutase (PGM) causes an accumulation of glucose 1-phosphate when yeast cells are grown with galactose as the carbon and energy source. Remarkably, the pgm2 strain also exhibits a severe imbalance in intracellular Ca²⁺ homeostasis when grown under these conditions. In the present study, we examined how the pgm2 mutation alters yeast Ca²⁺ homeostasis in greater detail. We found that a shift from glucose to galactose as the carbon source resulted in a 2-fold increase in the rate of cellular Ca²⁺ uptake in wild-type cells, whereas Ca²⁺ uptake increased 8-fold in the pgm2 mutant. Disruption of the PMC1 gene, which encodes the vacuolar Ca²⁺-ATPase Pmc1p, suppressed the Ca²⁺-related phenotypes observed in the pgm2 strain. This suggests that excessive vacuolar Ca²⁺ uptake is tightly coupled to these defects in Ca²⁺ homeostasis. An in vitro assay designed to measure Ca²⁺ sequestration into intracellular compartments confirmed that the pgm2 mutant contained a higher level of Pmc1p-dependent Ca²⁺ transport activity than the wild-type strain. We found that this increased rate of vacuolar Ca²⁺ uptake also coincided with a large induction of the unfolded protein response in the pgm2 mutant, suggesting that Ca²⁺ uptake into the endoplasmic reticulum compartment was reduced. These results indicate that the excessive Ca²⁺ uptake and accumulation previously shown to be associated with the pgm2 mutation are due to a severe imbalance in the distribution of cellular Ca²⁺ into different intracellular compartments.

Received for publication, January 26, 2004 , and in revised form, June 18, 2004.

^* This work was supported by National Institutes of Health Grant T32 HL07553 (to D. P. A.), American Heart Association Grant 0255121B (to D. M. B.), and Hungarian National Science Foundation Grant T-038144 (to A. M.). 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.

These authors contributed equally to this work and should be considered co-first authors.

^** To whom correspondence should be addressed: Dept. of Microbiology, BBRB 432/Box 8, 1530 Third Ave., South, The University of Alabama at Birmingham, Birmingham, AL 35294-2170. Tel.: 205-934-6593; Fax: 205-975-5482; E-mail: dbedwell{at}uab.edu.

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