Gating mechanisms of the type-1 inositol trisphosphate receptor

¹ University of Medicine and Pharmacology

^* To whom correspondence should be addressed. E-mail: baran{at}theor1.theory.nipne.ro.

Submitted on January 7, 2005
Revised on March 17, 2005
Accepted on 11 May 2005

	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 IP3 can be explained by assuming one activation and one inhibition modules, both operated by allosteric interactions between Ca2+, IP3 and ATP, and one adaptation element, driven by IP3, Ca2+, and the interconversion between two possible conformations of the receptor. This module becomes completely insensitive to a second IP3 pulse within 80 seconds. 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 uM and one-order higher at 0.02 uM IP3, whereas at 180 uM IP3 the maximal in vivo activity may be 2.5 higher than in bilayers and restricted to a narrower Ca2+ domain (~ 10 uM- vs. ~ 100 uM-wide). IP3 is likely to inhibit channel activity at <= 120 nM Ca2+ in vivo.

Key Words: calcium release, channel gating, channel inactivation, inositol 1,4,5-trisphosphate, model