J. theor. Biol. (1985) 115, 337-349 Mechanisms of Apparent Affinity Variation of Guarded Receptors C. FRANK STARMER AND MlCHAEL D. HOLLETT Departments of Medicine and Computer Science, Duke University Medical Center, Durham, North Carolina 27710, U.S.A. (Received 26 January 1984, and in revised form 25 September 1984) Studies of interactions between blocking agents such as antiarrhythmic drugs and gated ion channels have suggested apparent variations in binding site affinity. In this report, we develop a model by which these properties of ion channels can be explained simply on the fact that blocking agent access to the channel receptor is regulated by the channel gating apparatus. We view ion channel blockade as a two stage process: diffusion of drug to a region near the channel binding site and coupling of drug to the binding site resulting in a non-conducting, drug complexed channel. We define a guarded receptor as a receptor where binding site access is regulated by some process such as gated control of the ligand diffusion path. Relation- ships for equilibrium properties of guarded receptors differ from those of traditional unguarded receptors. With periodic activation of channel gates, as in cardiac muscle, a true equilibrium may never be reached due to transient receptor access. Lack of equilibrium can complicate analysis. For gated ion channels we derive equilibrium block properties under conditions of no stimulation. We show that a fixed affinity guarded receptor appears as an apparent variable affinity receptor in gated channels. These results are consistent with observations of apparent variations in receptor affinity derived from studies of local anesthetics in cardiac muscle. Furthermore, by separating drug diffusion and receptor binding, this description may facilitate quantitative characterization of local anesthetics and antiarrhyth- mia drugs in excitable membranes. Introduction In excitable membranes, patterns of electrical response elicited by a sequence of stimuli show variation in the presence of local anesthetic (Weidmann, 1955; Johnson & McKinnon, 1957; Armstrong, 1969; Strichartz, 1973; Courtney, 1975; Hondeghem & Katzung, 1977). To account for the variation in membrane response, several mechanisms have been proposed, including a variable affinity receptor within the sodium channel and modified gating kinetics in drug-complexed channels (Hille, 1977; Hondeghem & Katzung, 1977). In particular, Hille (1977) and, indepen- dently, Hondeghem & Katzung (1977), proposed a modulated receptor 337 0022-5193/85/150337+ 13 $03.00/0 ~) 1985 Academic Press Inc. (London) Ltd