title: Gene knock-outs of inositol 1,4,5-trisphosphate receptors types 1 and 2 result in perturbation of cardiogenesis.
abstract: BACKGROUND
  Inositol 1,4,5-trisphosphate receptors (IP3R1, 2, and 3) are intracellular Ca2+ release channels that regulate various 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.
  
  
  RESULTS
  We found that IP3R1(-/-)-IP3R2(-/-) 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 IP3R1(-/-) or IP3R2(-/-) single-mutant mice at this developmental stage. The double-mutant 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
  Our results suggest an essential role for IP3Rs in cardiogenesis in part through the regulation of calcineurin-NFAT signaling.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Uchida
authors.forename: Megumi
authors.initials: M
authors.lastname: Aramaki
authors.forename: Maki
authors.initials: M
authors.lastname: Nakazawa
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamagishi
authors.forename: Shinji
authors.initials: S
authors.lastname: Makino
authors.forename: Keiichi
authors.initials: K
authors.lastname: Fukuda
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Takao
authors.initials: T
authors.lastname: Takahashi
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamagishi
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018507:Gene Expression Regulation, Developmental; D055786:Gene Knockout Techniques; D006321:Heart / Q000196:embryology*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors
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