Gating mechanisms of the type-1 inositol trisphosphate receptor

Abstract

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 IP 3 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 Ca 2+ in vivo. © 2005 by the Biophysical Society.