Gating Mechanisms of the Type-1 Inositol Trisphosphate Receptor

AbstractA 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 80s. 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 59s in the activation, and 0.75s 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 2μM and one-order-higher at 0.02μM IP3, whereas at 180μM IP3 the maximal in vivo activity may be 2.5-orders higher than in bilayers and restricted to a narrower Ca2+ domain (∼10μM-wide versus ∼100μM-wide). IP3 is likely to inhibit channel activity at ≤120nM Ca2+ in vivo