A rise in intracellular calcium ([Ca2+]i) in response to binding of inositol 1,4,5 trisphosphate (InsP3) to its receptors is a ubiquitous signaling system, which is implicated in the control of a myriad of cellular functions (
It has been tempting to speculate that many characteristics of these specific [Ca2+]i signals are due to the differential regulation of individual InsP3 receptor subtypes 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 subtype-specific regulation of InsP3 receptors by perhaps its most important regulator, calcium. By patch clamping the outer nuclear membrane of isolated Xenopus laevis nuclei, Mak et al. (2001
Of particular note, the major defining difference between the type-1 and type-3 receptors reported by
Mak et al., 2001b report a critical role for ATP in conferring the absolute and, thus, differential sensitivity of the two receptor types to Ca2+. At zero ATP and saturating [InsP3], both receptors are reported to have identical Ca2+ sensitivity. As the [ATP] is increased, the Ca2+ concentration for half-maximal activation of each receptor decreases markedly. This effect occurred disproportionately, such that at levels of ATP thought to be close to physiological (0.5 mM) the type-3 receptor, when compared to the type-1 receptor, now exhibited increased sensitivity to activation by Ca2+ and no cooperativity.
The differential sensitivity of the two channel types to Ca2+ and ATP has obvious implications for the role these channels play in the repertoire of calcium signals observed in nonexcitable cells. Resting [Ca2+]i is generally reported to be in the range between 30 and 150 nM, such that the [Ca2+] for half-maximal activation of the type-1 and type-3 receptors is poised on either side of the basal [Ca2+]i, hinting at distinct functional roles for the two receptors. For example, the Ca2+ sensitivity and lack of cooperativity of the type-3 receptor results in high open probability upon binding of InsP3 at or near resting levels of Ca2+. Therefore, the type-3 receptor, is ideally suited to act as an initial trigger for Ca2+ release, as originally suggested by Ehrlich and colleagues (
At threshold agonist concentrations, where very low InsP3 levels are likely to be generated, [Ca2+]i signals often are confined to a region close to the initiation sites, even without a contribution of active buffering systems such as mitochondria (1 µM), highly localized elevations of [Ca2+]i have been reported upon threshold stimulation (
Although the type-3 receptor exhibits properties that make it ideally suited for the initial trigger, it may not satisfy the requirements for regenerative release. For example, a further increase in Ca2+ will increase channel open probability less than threefold and, thus, the dynamic range of CICR is limited (
The modulation of InsP3 receptors by ATP over a physiologically relevant range is particularly noteworthy (
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