A dynamic model of the type-2 inositol trisphosphate receptor.
The dynamic properties of the inositol (1,4,5)-trisphosphate (IP(3)) receptor are crucial for the control of intracellular Ca(2+), including the generation of Ca(2+) oscillations and waves. However, many models of this receptor do not agree with recent experimental data on the dynamic responses of the receptor. We construct a model of the IP(3) receptor and fit the model to dynamic and steady-state experimental data from type-2 IP(3) receptors. Our results indicate that, (i) Ca(2+) binds to the receptor using saturating, not mass-action, kinetics; (ii) Ca(2+) decreases the rate of IP(3) binding while simultaneously increasing the steady-state sensitivity of the receptor to IP(3); (iii) the rate of Ca(2+)-induced receptor activation increases with Ca(2+) and is faster than Ca(2+)-induced receptor inactivation; and (iv) IP(3) receptors are sequentially activated and inactivated by Ca(2+) even when IP(3) is bound. Our results emphasize that measurement of steady-state properties alone is insufficient to characterize the functional properties of the receptor.
Sneyd
James
J
Institute of Information and Mathematical Sciences, Massey University, Albany Campus, Private Bag 102-904, North Shore Mail Centre, Auckland, New Zealand. jsneyd@massey.ac.nz
Dufour
Jean-Francois
JF
D000818:Animals; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000737:chemistry* / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D053496:Inositol 1,4,5-Trisphosphate Receptors; D007700:Kinetics; D008956:Models, Chemical; D009991:Oscillometry; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000737:chemistry* / Q000378:metabolism*; D013997:Time Factors; D014981:Xenopus
D015220:Calcium Channels; D053496:Inositol 1,4,5-Trisphosphate Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D002118:Calcium