Isoform-specific function of single inositol 1,4,5-trisphosphate receptor channels

The inositol 1,4,5-trisphosphate receptor (InsP(3)R) family of Ca2+ release channels is central to intracellular Ca2+ signaling in mammalian cells. The InsP(3)R channels release Ca2+ from intracellular compartments to generate localized Ca2+ transients that govern a myriad of cellular signaling phenomena (Berridge, 1993, Nature. 361:315-325; Joseph, 1996, Cell Signal. 8:1-7; Kume et al,, 1997, Science. 278:1940-1943; Berridge, 1997, Nature. 368:759-760), Most cells express multiple InsP(3)R isoforms, but only the function of the single type 1 InsP(3)R channel is known. Here the single-channel function of single type 2 InsP(3)R channel is defined for the first time. The type 2 InsP(3)R forms channels with permeation properties similar to that of the type 1 receptor. The InsP(3) regulation and Ca2+ regulation of type 1 and type 2 InsP(3)R channels are strikingly different. Both InsP(3) and Ca2+ are more effective at activating single type 2 InsP(3)R, indicating that single type 2 channels mobilize substantially more Ca2+ than single type 1 channels in cells. Furthermore, high cytoplasmic Ca2+ concentrations inactivate type 1, but not type 2, InsP(3)R channels. This indicates that type 2 InsP(3)R channel is different from the type 1 channel in that its activity will not be inherently self-limiting, because Ca2+ passing through an active type 2 channel cannot feed back and turn the channel off. Thus the InsP(3)R identity will help define the spatial and temporal nature of local Ca2+ signaling events and may contribute to the segregation of parallel InsP(3) signaling cascades in mammalian cells.