Voltage- and SOCS channels are the major routes of Ca(2+) entry in mammalian cells and a negative reciprocal interaction between these channels has been described (Doltmetsch et al., 2010). We have previously reported (Gonzalez et al., 2010) that preconditioning in heart leads to down-regulation of Cav1.2 channels. In the present experiments we examined the changes that take place by preconditioning in the expression and function of STIM1 and Orai1, major components of SOCS in heart. We measured membrane currents with the whole-cell patch-clamp technique. To assess the effect of preconditioning on SOCS, protein expression levels of STIM1 and Orai1 were measured by Western blotting and confocal microscopy, and intracellular Ca(2+) measurements was quantitated by Fura-2. Diazoxide (100 uM), was used to induce pharmacological preconditioning. Ischemic preconditioning was produced by brief periods of ischemia. Depletion of internal stores was achieved with thapsigargin. Both forms of preconditioning greatly reduced infaction areas relative to controls. Store depletion generated Ca(2+) selective currents with strong inward rectification. Preconditioning almost completely suppressed these currents, an effect that was almost blocked by 5HD a selective mitoKATP channel blocker and by intracellular BAPTA. And as assessed by Fura-2 this influx was also blocked by preconditioning. In contrast, the expression at the protein level of both STIM1 and Orai1 was strongly up-regulated by preconditioning and confocal microscopy revealed a higher density of Orai1 channels at the surface membrane. Our results indicate that while the expression of protein components of SOCS in heart cells (STIM1 and Orai1) are up-regulated by preconditioning, influx of Ca(2+) through SOCS is severely impaired by preconditioning, probably by a slow Ca(2+)-dependent inactivation process. Supported by CONACYT, grant 284053 to JS.