Gating mechanisms of the type-1 inositol trisphosphate receptor.

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 microM and one-order-higher at 0.02 microM IP(3), whereas at 180 microM IP(3) the maximal in vivo activity may be 2.5-orders higher than in bilayers and restricted to a narrower Ca(2+) domain (approximately 10 microM-wide versus approximately 100 microM-wide). IP(3) is likely to inhibit channel activity at < or =120 nM Ca(2+) in vivo.