Modeling Ca2+ feedback on a single inositol 1,4,5-trisphosphate receptor and its modulation by Ca2+ buffers.
The inositol 1,4,5-trisphosphate receptor/channel (IP(3)R) is a major regulator of intracellular Ca(2+) signaling, and liberates Ca(2+) ions from the endoplasmic reticulum in response to binding at cytosolic sites for both IP(3) and Ca(2+). Although the steady-state gating properties of the IP(3)R have been extensively studied and modeled under conditions of fixed [IP(3)] and [Ca(2+)], little is known about how Ca(2+) flux through a channel may modulate the gating of that same channel by feedback onto activating and inhibitory Ca(2+) binding sites. We thus simulated the dynamics of Ca(2+) self-feedback on monomeric and tetrameric IP(3)R models. A major conclusion is that self-activation depends crucially on stationary cytosolic Ca(2+) buffers that slow the collapse of the local [Ca(2+)] microdomain after closure. This promotes burst-like reopenings by the rebinding of Ca(2+) to the activating site; whereas inhibitory actions are substantially independent of stationary buffers but are strongly dependent on the location of the inhibitory Ca(2+) binding site on the IP(3)R in relation to the channel pore.
Shuai
Jianwei
J
Department of Physics, Xiamen University, Xiamen, China. jianweishuai@xmu.edu.cn
Pearson
John E
JE
Parker
Ian
I
D000818:Animals; D002021:Buffers; D002118:Calcium / Q000378:metabolism*; D003600:Cytosol / Q000378:metabolism; D025461:Feedback, Physiological; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000737:chemistry / Q000378:metabolism*; D008954:Models, Biological; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D014981:Xenopus / Q000378:metabolism*
D002021:Buffers; D053496:Inositol 1,4,5-Trisphosphate Receptors; D021122:Protein Subunits; D002118:Calcium