The internal
ionic environment of the endoplasmic reticulum is regulated to
accommodate many essential cellular processes. The mechanisms by which
calcium concentration in the ER lumen is controlled remain enigmatic,
although the golgi-localized P-type ATPase Pmr1p has been shown to
play a role. We have recently described another P-type ATPase
Cod1p/Spf1p (for control of HMG-CoA reductase degradation) that is
required for regulating HMG-CoA reductase (Hmg2p) degradation in the
ER. From the phenotypes of the cod1 mutant, we hypothesize that
Cod1p is an ER calcium transporter. Consistent with this, Cod1p
localized to the ER and deletion of cod1 activated
calcineurin-inducible genes. Deletion of both COD1 and
PMR1 produced a six-fold increase in total cellular calcium,
but did not affect the level of other ions. Importantly, null mutants
of PMR1 and COD1 had distinct phenotypes. For example,
pmr1 mutants tolerated deletion of HAC1, whereas
cod1 mutants required this gene for viability. Taken together,
our observations support a role for Cod1p in the regulation of ER
calcium and challenge the idea that Pmr1p is the only P-type ATPase
controlling the concentration of calcium in the secretory pathway. We
are currently attempting to directly determine the ionic substrate(s)
of Cod1p.
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