The role of agonist-independent conformational transformation (AICT) in IP₃ cluster behavior

Inositol 1,4,5-trisphosphate (IP(3)) receptor is a central unit in intracellular Ca(2+) signaling. Regulation of the IP₃ receptor by calcium is well characterized. High open probability values are reported for a single IP₃ receptor in nuclear patch clamp experiments. These experimental observations are in contrast with the lower open probability values of the lipid bilayer experiments. Most theoretical models do not account for high open probabilities of the receptor. But more recently, new models of the IP₃ receptor have been put forward which are constrained by single-channel nuclear patch clamp recordings, which generate the larger open probability with the aid of an additional agonist-independent conformational transformation (AICT)-'active' state. The main aim of this work is to constrain the AICT models with a wealth of experimental data characterizing calcium release from IP₃ receptor clusters. Our results suggest that consistency of cluster release between theory and experiments constrains the kinetics of the agonist-independent conformational transition rates (AICT) to values which lead to small open probabilities for the IP₃ receptor inconsistent with nuclear patch clamp experimental data.