Background/Aims: The inositol 1,4,5-trisphosphate receptor (IP3R), a ligand-gated Ca2+ channel, plays an important role in the control of intracellular Ca2+. Three isoforms of IP3R have been identified and most cell types express different proportions of these isoforms. The purpose of this study was to investigate how IP3R signalling is involved in the activation of the Ca2+-sensitive transcription factors NFAT and CREB. Methods: Each IP3R isoform expressed in HEK 293A cells was knocked down using selective siRNA. Free intracellular Ca2+ was monitored spectrofluometrically. NFAT and CREB activities were measured with luciferase reporter constructs. Results: IP3R-2-knocked down HEK 293A cells showed a deficient CCh-induced Ca2+ response that could be rescued by co-stimulation with VIP, a cAMP increasing agonist. NFAT transcriptional activity, but not CREB transcriptional activity, was significantly reduced in IP3R-2-knocked down HEK 293A cells. Overexpression of IP3R-1 could fully compensate for IP3R-2 knock down to mobilize Ca2+ and to activate NFAT. Conclusion: Our results show that the knock down of IP3R-2 significantly reduced the intracellular Ca2+ response of HEK 293 cells. This reduced Ca2+ response did not affect the activation of CREB but significantly decreased the activation of NFAT, suggesting that the Ca2+ signals required for the activation of NFAT are stronger than those required for the activation of CREB.

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