A conserved family of calcineurin regulators

The protein phosphatase calcineurin mediates many cellular responses to cal cium signals. Using a genetic screen in yeast, we identified a new family o f proteins conserved in fungi and animals that inhibit calcineurin function when overexpressed. Overexpression of the yeast protein Rcn1p or the human homologs DSCR1 or ZAKI-4 inhibited two independent functions of calcineuri n in yeast: The activation of the transcription factor Tcn1p and the inhibi tion of the H+/Ca2+ exchanger Vcx1p. Purified recombinant Rcn1p and DSCR1 b ound calcineurin in vitro and inhibited its protein phosphatase activity. S ignaling via calmodulin, calcineurin, and Tcn1p induced Rcn1p expression, s uggesting that Rcn1p operates as an endogenous feedback inhibitor of calcin eurin. Surprisingly, rcn1 null mutants exhibited phenotypes similar to thos e of Rcn1p-overexpressing cells. This effect may be due to lower expression of calcineurin in rcn1 mutants during signaling conditions. Thus, Rcn1p le vels may fine-tune calcineurin signaling in yeast. The structural and funct ional conservation between Rcn1p and DSCR1 suggests that the mammalian Rcn1 p-related proteins, termed calcipressins, will modulate calcineurin signali ng in humans and potentially contribute to disorders such as Down Syndrome.