Subtype-Specific Regulation of Inositol 1,4,5-Trisphosphate Receptors

A rise in intracellular calcium ([Ca 2 ϩ ] i) in response to binding of inositol 1,4,5 trisphosphate (InsP 3) to its receptors is a ubiquitous signaling system, which is implicated in the control of a myriad of cellular functions (Berridge, 1993). Three distinct InsP 3 receptors are expressed to varying degrees in individual cell types (Wojcikiewicz, 1995). Activation of these receptors results in [Ca 2 ϩ ] i signals that display impressive fidelity, frequently manifested through a complex array of temporal and spatial characteristics. [Ca 2 ϩ ] i signals in non-excitable cells are initiated in defined regions (Kasai and Augustine 1990; Rooney et al., 1990); can be spatially limited to a portion of a cell (Kasai et al., 1993) or alternatively spread as repetitive, global, oscillatory waves throughout an entire cell (Lechleiter et al., 1991; Straub et al., 2000). In addition, the periodicity of these spatial events is tightly regulated and has been proposed to provide effectors with a digitally encoded signal. It has been tempting to speculate that many characteristics of these specific [Ca 2 ϩ ] i signals are due to the differential regulation of individual InsP 3 receptor sub-types expressed in a given cell. However, this idea has been difficult to test because individual receptor types are rarely found in isolation, without " contamination " from other receptor types. Two papers in this issue of The Journal have elegantly addressed the issue of sub-type-specific regulation of InsP 3 receptors by perhaps its most important regulator, calcium. By patch clamping the outer nuclear membrane of isolated Xenopus laevis nuclei, Mak et al. (2001 a,b) studied the activity of the type-3 receptor and its regulation by Ca 2 ϩ and InsP 3. Using an " on nucleus " patch-clamp configuration analogous to the " on cell " configuration conventionally used in intact cells, the authors investigated the effects of InsP 3 , Ca 2 ϩ , and ATP on InsP 3 receptor single-channel activity. Because the outer nuclear membrane is contiguous with the endoplasmic reticulum (ER), InsP 3 receptor channel activity can be assessed in an essentially native membrane environment. The authors transfected type-3 InsP 3 receptor into oocytes expressing extremely low levels of endogenous (type-1) receptor such that the activity of type-3 receptor could be assessed on an essentially null background, and then subsequently compared with the properties of the type-1 receptor. Previous studies have showed …