Gene knock-outs of inositol 1,4,5-trisphosphate receptors types 1 and 2 result in perturbation of cardiogenesis

Background: Inositol 1,4,5-trisphosphate receptors (IP₃R1, 2, and 3) are intracellular Ca²⁺ release channels that regulatevarious vital processes. Although the ryanodine receptor type 2, another type of intracellular Ca²⁺ release channel, has been shown to play a role in embryonic cardiomyocytes, the functions of the IP3Rs in cardiogenesis remain unclear. Methodology/Principal Findings: We found that IP₃R1^-/-IP₃R22/2 double-mutant mice died in utero with developmental defects of the ventricular myocardium and atrioventricular (AV) canal of the heart by embryonic day (E) 11.5, even though no cardiac defect was detectable in IP3R12/2 or IP3R22/2 single-mutant mice at this developmental stage. The doublemutant phenotype resembled that of mice deficient for calcineurin/NFATc signaling, and NFATc was inactive in embryonic hearts from the double knockout-mutant mice. The double mutation of IP3R1/R2 and pharmacologic inhibition of IP3Rs mimicked the phenotype of the AV valve defect that result from the inhibition of calcineurin, and it could be rescued by constitutively active calcineurin. Conclusions/Significance: Our results suggest an essential role for IP₃Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling.