Biophys J, August 1998, p. 834-839, Vol. 75, No. 2

Isoform-Specific Function of Single Inositol 1,4,5-Trisphosphate Receptor Channels

 ^*Loyola University Chicago, Stritch School of Medicine, Department of Physiology, and Cardiovascular Institute, Maywood, Illinois 60153 USA

The inositol 1,4,5-trisphosphate receptor (InsP₃R) family of Ca²⁺ release channels is central to intracellular Ca²⁺ signaling in mammalian cells. The InsP₃R 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 InsP₃R isoforms, but only the function of the single type 1 InsP₃R channel is known. Here the single-channel function of single type 2 InsP₃R channel is defined for the first time. The type 2 InsP₃R forms channels with permeation properties similar to that of the type 1 receptor. The InsP₃ regulation and Ca²⁺ regulation of type 1 and type 2 InsP₃R channels are strikingly different. Both InsP₃ and Ca²⁺ are more effective at activating single type 2 InsP₃R, 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, InsP₃R channels. This indicates that type 2 InsP₃R 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 InsP₃R identity will help define the spatial and temporal nature of local Ca²⁺ signaling events and may contribute to the segregation of parallel InsP₃ signaling cascades in mammalian cells.

Biophys J, August 1998, p. 834-839, Vol. 75, No. 2
© 1998 by the Biophysical Society   0006-3495/98/08/834/06  $2.00

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