Calcineurin-dependent growth control in Saccharomyces cerevisiae mutants lacking PMC1, a homolog of plasma membrane Ca2+ ATPases

• Published in: The Journal of cell biology 1994-02, Vol.124 (3), p.351-363
• Main Authors: Cunningham, K.W, Fink, G.R
• Format: Article
• Language: English
• Subjects: ADENOSINA TRIFOSFATASA; ADENOSINE TRIPHOSPHATASE; Adenosine triphosphatases; Amino Acid Sequence; Base Sequence; Biological and medical sciences; Calcineurin; CALCIO; CALCIUM; Calcium - metabolism; Calcium - pharmacology; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Calmodulin - pharmacology; Calmodulin-Binding Proteins - antagonists & inhibitors; Calmodulin-Binding Proteins - metabolism; CATION; CATIONES; Cell cycle, cell proliferation; Cell Membrane - enzymology; Cell membranes; Cell physiology; Cells; Cloning, Molecular; CRECIMIENTO; CROISSANCE; Cyclosporine - pharmacology; Cyclosporins; Enzyme Activation; ESTERASAS; ESTERASE; Fundamental and applied biological sciences. Psychology; Fungal Proteins - genetics; Fungal Proteins - metabolism; GENE; GENES; Genes, Fungal; Genetic mutation; HIDROLASAS; HYDROLASE; ION; IONES; Molecular and cellular biology; Molecular Sequence Data; MUTACION INDUCIDA; MUTANT; MUTANTES; Mutation; MUTATION PROVOQUEE; Phosphoprotein Phosphatases - antagonists & inhibitors; Phosphoprotein Phosphatases - metabolism; Plasma Membrane Calcium-Transporting ATPases; Plasmids; PROTEINAS; PROTEINE; SACCHAROMYCES CEREVISIAE; Saccharomyces cerevisiae - genetics; Saccharomyces cerevisiae - growth & development; Saccharomyces cerevisiae - metabolism; Saccharomyces cerevisiae Proteins; SECUENCIA NUCLEICA; SEQUENCE NUCLEIQUE; T lymphocytes; Tacrolimus - pharmacology; Vacuoles; Yeasts
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.124.3.351

Ca2+ ATPases deplete the cytosol of Ca2+ ions and are crucial to cellular Ca2+ homeostasis. The PMC1 gene of Saccharomyces cerevisiae encodes a vacuole membrane protein that is 40% identical to the plasma membrane Ca2+ ATPases (PMCAs) of mammalian cells. Mutants lacking PMC1 grow well in standard media, but sequester Ca2+ into the vacuole at 20% of the wild-type levels. pmc1 null mutants fail to grow in media containing high levels of Ca2+, suggesting a role of PMC1 in Ca2+ tolerance. The growth inhibitory effect of added Ca2+ requires activation of calcineurin, a Ca2+ and calmodulin-dependent protein phosphatase. Mutations in calcineurin A or B subunits or the inhibitory compounds FK506 and cyclosporin A restore growth of pmc1 mutants in high Ca2+ media. Also, growth is restored by recessive mutations that inactivate the high-affinity Ca2+-binding sites in calmodulin. This mutant calmodulin has apparently lost the ability to activate calcineurin in vivo. These results suggest that activation of calcineurin by Ca2+ and calmodulin can negatively affect yeast growth. A second Ca2+ ATPase homolog encoded by the PMR1 gene acts together with PMC1 to prevent lethal activation of calcineurin even in standard (low Ca+) conditions. We propose that these Ca2+ ATPase homologs are essential in yeast to deplete the cytosol of Ca+ ions which, at elevated concentrations, inhibits yeast growth through inappropriate activation of calcineurin