Stochastic simulation of a single inositol 1,4,5-trisphosphate-sensitive Ca2+ channel reveals repetitive openings during 'blip-like' Ca2+ transients.
Confocal microscope studies with fluorescent dyes of inositol 1,4,5-trisphosphate (InsP3)-induced intracellular Ca2+ mobilization recently established the existence of 'elementary' events, dependent on the activity of individual InsP3-sensitive Ca2+ channels. In the present work, we try by theoretical stochastic simulation to explain the smallest signals observed in those studies, which were referred to as Ca2+ 'blips' [Parker I., Yao Y. Ca2+ transients associated with openings of inositol trisphosphate-gated channels in Xenopus oocytes. J Physiol Lond 1996; 491: 663-668]. For this purpose, we assumed a simple molecular model for the InsP3-sensitive Ca2+ channel and defined a set of parameter values accounting for the results obtained in electrophysiological bilayer experiments [Bezprozvanny I., Watras J., Ehrlich B.E. Bell-shaped calcium-response curves of Ins(1,4,5)P3- and calcium-gated channels from endoplasmic reticulum of cerebellum. Nature 1991; 351: 751-754; Bezprozvanny I., Ehrlich B.E. Inositol (1,4,5)-trisphosphate (InsP3)-gated Ca channels from cerebellum: conduction properties for divalent cations and regulation by intraluminal calcium. J Gen Physiol 1994; 104: 821-856]. With a stochastic procedure which considered cytosolic Ca2+ diffusion explicitly, we then simulated the behaviour of a single channel, placed in a realistic physiological environment. An attractive result was that the simulated channel exhibited bursts of activity, arising from repetitive channel openings, which were responsible for transient rises in Ca2+ concentration and were reminiscent of the relatively long-duration experimental Ca2+ blips. The influence of the values chosen for the various parameters (affinity and diffusion coefficient of the buffers, luminal Ca2+ concentration) on the kinetic characteristics of these theoretical blips is analyzed.
Swillens
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Institut de Recherche Interdisciplinaire, Faculté de Médecine, Université Libre de Bruxelles, Belgium. swillens@ulb.ac.be
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Combettes
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Dupont
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D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000737:chemistry / Q000187:drug effects*; D002531:Cerebellum / Q000378:metabolism; D003198:Computer Simulation; D003600:Cytosol / Q000378:metabolism; D004058:Diffusion; D005456:Fluorescent Dyes / Q000378:metabolism; D015544:Inositol 1,4,5-Trisphosphate / Q000494:pharmacology*; D015640:Ion Channel Gating; D017136:Ion Transport; D007700:Kinetics; D008051:Lipid Bilayers / Q000378:metabolism; D008954:Models, Biological; D009930:Organic Chemicals; D013269:Stochastic Processes
D015220:Calcium Channels; D005456:Fluorescent Dyes; D008051:Lipid Bilayers; D009930:Organic Chemicals; C071336:calcium green; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium