title: Distinct roles of inositol 1,4,5-trisphosphate receptor types 1 and 3 in Ca2+ signaling.
abstract: Three subtypes of inositol 1,4,5-trisphosphate receptor (IP(3)R1, IP(3)R2, and IP(3)R3) Ca(2+) release channel share basic properties but differ in terms of regulation. To what extent they contribute to complex Ca(2+) signaling, such as Ca(2+) 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 Ca(2+) signaling patterns. Knockdown of IP(3)R1 significantly decreases total Ca(2+) signals and terminates Ca(2+) oscillations. Conversely, knockdown of IP(3)R3 leads to more robust and long lasting Ca(2+) oscillations than in controls. Effects of IP(3)R3 knockdown are surprisingly similar in COS-7 cells that predominantly (>90% of total IP(3)R) express IP(3)R3, suggesting that IP(3)R3 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 IP(3)R subtype is critical for various forms of Ca(2+) signaling, and, particularly, IP(3)R1 and IP(3)R3 have opposite roles in generating Ca(2+) oscillations.
authors.affiliation: Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, 4-1-8, Hon-machi, Kawaguchi, Saitama 332-0012, Japan. mhattori@ims.u-tokyo.ac.jp
authors.forename: Mitsuharu
authors.initials: M
authors.lastname: Hattori
authors.forename: Akinobu Z
authors.initials: AZ
authors.lastname: Suzuki
authors.forename: Takayasu
authors.initials: T
authors.lastname: Higo
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miyauchi
authors.forename: Takayuki
authors.initials: T
authors.lastname: Michikawa
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nakamura
authors.forename: Takafumi
authors.initials: T
authors.lastname: Inoue
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Mikoshiba
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015220:Calcium Channels / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D006801:Humans; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000502:physiology*; D034622:RNA Interference; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry / Q000502:physiology*; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction
chemical_list: D015220:Calcium Channels; C506926:ITPR1 protein, human; D053496:Inositol 1,4,5-Trisphosphate Receptors; D020033:Protein Isoforms; D018160:Receptors, Cytoplasmic and Nuclear