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Gating Mechanisms of the Type-1 Inositol Trisphosphate Receptor

Biophysics Department, Faculty of Medicine, University of Medicine and Pharmacy "Carol Davila", Bucharest, Romania

Correspondence: Address reprint requests to Irina Baran, Tel.: 00-40-21-312-5955; E-mail: baran{at}theor1.theory.nipne.ro.

A large amount of data and observations on inositol 1,4,5-trisphosphate (IP₃) binding to the IP₃ receptor/Ca²⁺ channel, the steady-state activity of the channel, and its inactivation by IP₃ can be explained by assuming one activation and one inhibition module, both allosterically operated by Ca²⁺, IP₃, and ATP, and one adaptation element, driven by IP₃, Ca²⁺, and the interconversion between two possible conformations of the receptor. The adaptation module becomes completely insensitive to a second IP₃ pulse within 80 s. Observed kinetic responses are well reproduced if, in addition, two module open states are rendered inactive by the current charge carrier Mn²⁺. The inactivation time constants are 59 s in the activation, and 0.75 s in the adaptation module. The in vivo open probability of the channel is predicted to be almost in coincidence with the behavior in lipid bilayers for IP₃ levels of 0.2 and 2 µM and one-order-higher at 0.02 µM IP₃, whereas at 180 µM IP₃ the maximal in vivo activity may be 2.5-orders higher than in bilayers and restricted to a narrower Ca²⁺ domain (10 µM-wide versus 100 µM-wide). IP₃ is likely to inhibit channel activity at 120 nM Ca²⁺ in vivo.