Kw. Cunningham et Gr. Fink, CALCINEURIN INHIBITS VCX1-DEPENDENT H+ CA2+ EXCHANGE AND INDUCES CA2+ATPASES IN SACCHAROMYCES-CEREVISIAE/, Molecular and cellular biology, 16(5), 1996, pp. 2226-2237
The PMC1 gene in Saccharomyces cerevisiae encodes a vacuolar Ca2+ ATPa
se required for growth in high-Ca2+ conditions. Previous work showed t
hat Ca2+ tolerance can be restored to pmc1 mutants by inactivation of
calcineurin, a Ca2+/calmodulin-dependent protein phosphatase sensitive
to the immunosuppressive drug FK506. We now report that calcineurin d
ecreases Ca2+ tolerance of pmc1 mutants by inhibiting the function of
VCX1, which encodes a vacuolar H+/Ca2+ exchanger related to vertebrate
Na+/Ca2+ exchangers. The contribution of VCX1 in Ca2+ tolerance is lo
w in strains with a functional calcineurin and is high in strains whic
h lack calcineurin activity. In contrast, the contribution of PMC1 to
Ca2+ tolerance is augmented by calcineurin activation. Consistent with
these positive and negative roles of calcineurin, expression of a vcx
1::lacZ reporter was slightly diminished and a pmc1::lacZ reporter was
induced up to 500-fold by processes dependent on calcineurin, calmodu
lin, and Ca2+. It is likely that calcineurin inhibits VCX1 function ma
inly by posttranslational mechanisms, Activities of VCX1 and PMC1 help
to control cytosolic free Ca2+ concentrations because their function
can decrease pmc1::lacZ induction by calcineurin, Additional studies w
ith reporter genes and mutants indicate that PMR1 and PMR2A, encoding
P-type ion pumps required for Mn2+ and Na+ tolerance, may also be indu
ced physiologically in response to high-Mn2+. and -Na+ conditions thro
ugh calcineurin-dependent mechanisms. In these situations, inhibition
of VCX1 function may be important for the production of Ca2+ signals,
We propose that elevated cytosolic free Ca2+ concentrations, calmoduli
n, and calcineurin regulate at least four ion transporters in S. cerev
isiae in response to several environmental conditions.