title: 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 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.
authors.affiliation: Biophysics Department, Faculty of Medicine, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. baran@theor1.theory.nipne.ro
authors.forename: Irina
authors.initials: I
authors.lastname: Baran
mesh_terms: D001665:Binding Sites; D002118:Calcium / Q000737:chemistry*; D015220:Calcium Channels / Q000032:analysis / Q000737:chemistry*; D003198:Computer Simulation; D053496:Inositol 1,4,5-Trisphosphate Receptors; D015640:Ion Channel Gating; D008051:Lipid Bilayers / Q000737:chemistry*; D008956:Models, Chemical; D008958:Models, Molecular; D015233:Models, Statistical; D009038:Motion; D016062:Porosity; D011485:Protein Binding; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000032:analysis / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D008051:Lipid Bilayers; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium