Cooperation of calcineurin and vacuolar H(+)-ATPase in intracellular Ca2+ homeostasis of yeast cells.

Saccharomyces cerevisiae VMA genes, encoding essential components for the expression of vacuolar membrane H(+)-ATPase activity, are involved in intracellular ionic homeostasis and vacuolar biogenesis. We report here that the immunosuppressants FK506 and cyclosporin A cause general growth inhibition of the vma3 mutant. Upon addition of the drugs, the mutant grew ...
neither in the presence of more than 5 mM Ca2+ nor above pH 6.0. The action of the immunosuppressants is dependent on their binding proteins and ascribable to inhibition of calcineurin activity; a mutation of a calcineurin subunit (cnb1) shows synthetic lethal interaction with the vma mutation. The addition of FK506 decreases the cytosolic free concentration of Ca2+ in the vma3 mutant cells. Consequently, FK506 induces an 8.9-fold elevation of a nonexchangeable Ca2+ pool. These results suggest that calcineurin controls calcium homeostasis by repression of Ca2+ flux into a cellular compartment(s) and that the vacuolar H(+)-ATPase is essential for cell growth cooperating with calcineurin to regulate the cytosolic free concentration of Ca2+.
Mesh Terms:
Base Sequence, Calcineurin, Calcium, Calmodulin-Binding Proteins, Carrier Proteins, Cell Division, Cyclosporine, DNA Primers, DNA-Binding Proteins, Heat-Shock Proteins, Homeostasis, Hydrogen-Ion Concentration, Intracellular Membranes, Molecular Sequence Data, Mutation, Phosphoprotein Phosphatases, Proton-Translocating ATPases, Saccharomyces cerevisiae, Tacrolimus, Tacrolimus Binding Proteins, Vacuoles
J. Biol. Chem.
Date: Apr. 28, 1995
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