Three subtypes of inositol 1,4,5-trisphosphate receptor (IP3R1, IP3R2, and IP3R3) Ca2+ release channel share basic properties but differ in terms of regulation. To what extent they contribute to complex Ca2+ signaling, such as Ca2+ oscillations, remains largely unknown. Here we show that HeLa cells express comparable amounts of IP3R1 and IP3R3, but knockdown by RNA interference of each subtype results in dramatically distinct Ca 2+ signaling patterns. Knockdown of IP3R1 significantly decreases total Ca2+ signals and terminates Ca2+ oscillations. Conversely, knockdown of IP3R3 leads to more robust and long lasting Ca2+ oscillations than in controls. Effects of IP3R3 knockdown are surprisingly similar in COS-7 cells that predominantly (>90% of total IP3R) express IP3R3, suggesting that IP3R3 functions as an anti-Ca 2+-oscillatory unit without contributing to peak amplitude of Ca 2+ signals, irrespective of its relative expression level. Therefore, differential expression of the IP3R subtype is critical for various forms of Ca2+ signaling, and, particularly, IP3R1 and IP3R3 have opposite roles in generating Ca2+ oscillations.
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