Gating Mechanisms of the Type-1 Inositol Trisphosphate Receptor

Abstract

A large amount of data and observations on inositol 1,4,5-trisphosphate (IP 3) binding to the IP 3 receptor/Ca 2+ channel, the steady-state activity of the channel, and its inactivation by IP 3 can be explained by assuming one activation and one inhibition module, both allosterically operated by Ca 2+, IP 3, and ATP, and one adaptation element, driven by IP 3, Ca 2+, and the interconversion between two possible conformations of the receptor. The adaptation module becomes completely insensitive to a second IP 3 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 Mn 2+. 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 IP 3 levels of 0.2 and 2 μM and one-order-higher at 0.02 μM IP 3, whereas at 180 μM IP 3 the maximal in vivo activity may be 2.5-orders higher than in bilayers and restricted to a narrower Ca 2+ domain (∼10 μM-wide versus ∼100 μM-wide). IP 3 is likely to inhibit channel activity at ≤120 nM Ca 2+ in vivo.