Distinct roles of inositol 1,4,5-trisphosphate receptor types 1 and 3 in Ca2+ signaling

Three subtypes of inositol 1,4,5-trisphosphate receptor (IP(3)R1, IP(3)R2, and IP(3)R3) 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 IP(3)R1 and IP(3)R3, but knockdown by RNA interference of each subtype results in dramatically distinct Ca2+ signaling patterns. Knockdown of IP(3)R1 significantly decreases total Ca2+ signals and terminates Ca2+ oscillations. Conversely, knockdown of IP(3)R3 leads to more robust and long lasting Ca2+ oscillations than in controls. Effects of IP(3)R3 knockdown are surprisingly similar in COS-7 cells that predominantly (> 90% of total IP3R) express IP(3)R3, suggesting that IP(3)R3 functions as an anti-Ca2+-oscillatory unit without contributing to peak amplitude of Ca2+ signals, irrespective of its relative expression level. Therefore, differential expression of the IP3R subtype is critical for various forms of Ca2+ signaling, and, particularly, IP(3)R1 and IP(3)R3 have opposite roles in generating Ca2+ oscillations.