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Article

Simulation of Single Channel Kinetics Based on Ligand Binding and Electrophysiological Analysis

I.I. Moraru^*, E.J. Kaftan, B.E. Ehrlich, and J. Watras^*

From the ^* Departments of Medicine, Surgery, and Physiology, University of Connecticut, Farmington, Connecticut 06030; Department of Physiology and Biophysics, University of Washington, Seattle, Washington 98195; and Department of Pharmacology and Cellular & Molecular Physiology, Yale University, New Haven, Connecticut 06520

Cytosolic calcium acts as both a coagonist and an inhibitor of the type 1 inositol 1,4,5-trisphosphate (InsP₃)–gated Ca channel, resulting in a bell-shaped Ca dependence of channel activity (Bezprozvanny, I., J. Watras, and B.E. Ehrlich. 1991. Nature. 351:751–754; Finch, E.A., T.J. Turner, and S.M. Goldin. 1991. Science. 252: 443–446; Iino, M. 1990. J. Gen. Physiol. 95:1103–1122). The ability of Ca to inhibit channel activity, however, varies dramatically depending on InsP₃ concentration (Combettes, L., Z. Hannaert-Merah, J.F. Coquil, C. Rousseau, M. Claret, S. Swillens, and P. Champeil. 1994. J. Biol. Chem. 269:17561–17571; Kaftan, E.J., B.E. Ehrlich, and J. Watras. 1997. J. Gen. Physiol. 110:529–538). In the present report, we have extended the characterization of the effect of cytosolic Ca on both InsP₃ binding and InsP₃-gated channel kinetics, and incorporated these data into a mathematical model capable of simulating channel kinetics. We found that cytosolic Ca increased the K_d of InsP₃ binding 3.5-fold, but did not influence the maximal number of binding sites. The ability of Ca to decrease InsP₃ binding is consistent with the rightward shift in the bell-shaped Ca dependence of InsP₃-gated Ca channel activity. High InsP₃ concentrations are able to overcome the Ca-dependent inhibition of channel activity, apparently due to a low affinity InsP₃ binding site (Kaftan, E.J., B.E. Ehrlich, and J. Watras. 1997. J. Gen. Physiol. 110:529–538). Constants from binding analyses and channel activity determinations were used to develop a mathematical model that fits the complex Ca-dependent regulation of the type 1 InsP₃-gated Ca channel. This model accurately simulated both steady state data (channel open probability and InsP₃ binding) and kinetic data (channel activity and open time distributions), and yielded testable predictions with regard to the regulation of this intracellular Ca channel. Information gained from these analyses, and our current molecular model of this Ca channel, will be important for understanding the basis and regulation of intracellular Ca waves and oscillations in intact cells.

Key Words: cerebellum • inositol 1,4,5-trisphosphate receptor • intracellular calcium channel • calcium signaling • kinetic model

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