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J. Biol. Chem., Vol. 277, Issue 20, 17571-17579, May 17, 2002

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Fast Biphasic Regulation of Type 3 Inositol Trisphosphate Receptors by Cytosolic Calcium^*

Jane E. Swatton and Colin W. Taylor

From the Department of Pharmacology, University of Cambridge, Tennis Court Road, Cambridge CB2 1PD, United Kingdom

In cytosol-like medium (CLM) with a free [Ca²⁺] of 200 nM, a supramaximal concentration of inositol 1,4,5-trisphosphate (IP₃) (30 µM) evoked ⁴⁵Ca²⁺ release from type 3 IP₃ receptors only after a latency of 48 ± 6 ms; this latency could not be reduced by increasing the IP₃ concentration. In CLM containing a low free [Ca²⁺] (~4 nM), 300 µM IP₃ evoked ⁴⁵Ca²⁺ release after a latency of 66 ± 11 ms; this was reduced to 14 ± 3 ms when the [Ca²⁺] was 1 mM. Preincubation with CLM containing 100 µM Ca²⁺ caused a rapid (half-time = 33 ± 9 ms), complete, and fully reversible inhibition that could not be overcome by a high concentration of IP₃ (300 µM). Hepatic (type 2) IP₃ receptors were not inhibited by Ca²⁺ once they had bound IP₃, but 100 µM Ca²⁺ rapidly inhibited type 3 IP₃ receptors whether it was delivered before addition of IP₃ or at any stage during a response to IP₃. Ca²⁺ increases the affinity of IP₃ for hepatic receptors by slowing IP₃ dissociation, but Ca²⁺ had no effect on IP₃ binding to type 3 receptors. The rate of inhibition of type 3 IP₃ receptors by Ca²⁺ was faster than the rate of IP₃ dissociation, and occurred at similar rates whether receptors had bound a high (adenophostin) or low affinity (3-deoxy-3-fluoro-IP₃) agonist. Dissociation of agonist is not therefore required for Ca²⁺ to inhibit type 3 IP₃ receptors. We conclude that type 2 and 3 IP₃ receptors are each biphasically regulated by Ca²⁺, but by different mechanisms. For both, IP₃ binding causes a stimulatory Ca²⁺-binding site to be exposed allowing Ca²⁺ to bind and open the channel. IP₃ binding protects type 2 receptors from Ca²⁺ inhibition, but type 3 receptors are inhibited by Ca²⁺ whether or not they have IP₃ bound. Increases in cytosolic [Ca²⁺] will immediately inhibit type 3 receptors, but inhibit type 2 receptors only after IP₃ has dissociated.

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