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

J Cell Biol. 1994 Feb;124(3):351-63. doi: 10.1083/jcb.124.3.351.

Abstract

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 Ca(2+)-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 Ca2+) conditions. We propose that these Ca2+ ATPase homologs are essential in yeast to deplete the cytosol of Ca2+ ions which, at elevated concentrations, inhibits yeast growth through inappropriate activation of calcineurin.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Base Sequence
  • Calcineurin
  • Calcium / metabolism*
  • Calcium / pharmacology
  • Calcium-Transporting ATPases / genetics
  • Calcium-Transporting ATPases / metabolism*
  • Calmodulin / pharmacology
  • Calmodulin-Binding Proteins / antagonists & inhibitors
  • Calmodulin-Binding Proteins / metabolism*
  • Cell Membrane / enzymology
  • Cloning, Molecular
  • Cyclosporine / pharmacology
  • Enzyme Activation
  • Fungal Proteins / genetics
  • Fungal Proteins / metabolism*
  • Genes, Fungal
  • Molecular Sequence Data
  • Mutation
  • Phosphoprotein Phosphatases / antagonists & inhibitors
  • Phosphoprotein Phosphatases / metabolism*
  • Plasma Membrane Calcium-Transporting ATPases
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / growth & development*
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins*
  • Tacrolimus / pharmacology

Substances

  • Calmodulin
  • Calmodulin-Binding Proteins
  • Fungal Proteins
  • PMC1 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • Cyclosporine
  • Calcineurin
  • Phosphoprotein Phosphatases
  • Plasma Membrane Calcium-Transporting ATPases
  • Calcium-Transporting ATPases
  • Calcium
  • Tacrolimus

Associated data

  • GENBANK/U03060