Mechanisms of apparent affinity variation of guarded receptors

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. Relationships 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 antiarrhythmia drugs in excitable membranes.