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Original Article

^a Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
Department of Physiology, B400 Richards Building, University of Pennsylvania, Philadelphia, PA 19104-6085.(215) 573-6808

foskett{at}mail.med.upenn.edu

A family of inositol 1,4,5-trisphosphate (InsP₃) receptor (InsP₃R) Ca²⁺ release channels plays a central role in Ca²⁺ signaling in most cells, but functional correlates of isoform diversity are unclear. Patch-clamp electrophysiology of endogenous type 1 (X-InsP₃R-1) and recombinant rat type 3 InsP₃R (r-InsP₃R-3) channels in the outer membrane of isolated Xenopus oocyte nuclei indicated that enhanced affinity and reduced cooperativity of Ca²⁺ activation sites of the InsP₃-liganded type 3 channel distinguished the two isoforms. Because Ca²⁺ activation of type 1 channel was the target of regulation by cytoplasmic ATP free acid concentration ([ATP]_i), here we studied the effects of [ATP]_i on the dependence of r-InsP₃R-3 gating on cytoplasmic free Ca²⁺ concentration ([Ca²⁺]_i). As [ATP]_i was increased from 0 to 0.5 mM, maximum r-InsP₃R-3 channel open probability (P_o) remained unchanged, whereas the half-maximal activating [Ca²⁺]_i and activation Hill coefficient both decreased continuously, from 800 to 77 nM and from 1.6 to 1, respectively, and the half-maximal inhibitory [Ca²⁺]_i was reduced from 115 to 39 µM. These effects were largely due to effects of ATP on the mean closed channel duration. Whereas the r-InsP₃R-3 had a substantially higher P_o than X-InsP₃R-1 in activating [Ca²⁺]_i (<1 µM) and 0.5 mM ATP, the Ca²⁺ dependencies of channel gating of the two isoforms became remarkably similar in the absence of ATP. Our results suggest that ATP binding is responsible for conferring distinct gating properties on the two InsP₃R channel isoforms. Possible molecular models to account for the distinct regulation by ATP of the Ca²⁺ activation properties of the two channel isoforms and the physiological implications of these results are discussed. Complex regulation by ATP of the types 1 and 3 InsP₃R channel activities may enable cells to generate sophisticated patterns of Ca²⁺ signals with cytoplasmic ATP as one of the second messengers.

Key Words: allosteric regulation • calcium release channel • single-channel electrophysiology • patch clamp • Xenopus oocyte

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				D. I. Yule Subtype-Specific Regulation of Inositol 1,4,5-Trisphosphate Receptors: Controlling Calcium Signals in Time and Space J. Gen. Physiol., May 1, 2001; 117(5): 431 - 434. [Full Text] [PDF]

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