Gap junction (GJ) channels form when two hexameric hemichannels from neighboring cells dock head-to-head, creating a continuous pore that directly connects their cytoplasms. This unique arrangement allows ions, small signaling molecules, and metabolites to pass between cells, thereby contributing to numerous physiological processes and disease mechanisms. The structural features of GJ channels confer distinct biophysical and functional properties. Unlike most voltage-gated ion channels that sense membrane voltage (V m ), GJ channels respond to the transjunctional voltage (V j ), defined as the difference between membrane voltages of coupled cells. Consequently, electrophysiological studies of GJ channels require dual whole-cell patch-clamp recordings, as their intercellular arrangement prevents direct access by conventional patch-clamp. Moreover, as GJ channel formation requires close apposition of cells, GJ channels tend to cluster in junctional plaques, often comprising dozens to thousands of channels. This complicates single-channel analyses and hampers cross-correlation with macroscopic currents. These obstacles have significantly hindered the advancement of quantitative models of GJ channel gating. To address these challenges, we combined electrophysiological recordings with mathematical/computational modeling. We first developed a minimal four-state model that could reproduce both steady-state and kinetic properties of gap junctional conductance in response to applied V j protocols. We then extended the model to analyze single-channel recordings using maximum likelihood methods. Additionally, we investigated the gating of unopposed connexin hemichannels, which are V m -sensitive rather than V j -sensitive but can likewise be described by a similar four-state model. These models provide analytical tools for investigating GJ channel biophysics, enabling comparisons of wild-type channels and disease-associated mutants. Moreover, these models can be applied to the simulation of excitable tissues. For example, we employed the models to explore impulse propagation in neurons coupled by electrical synapses and in cardiomyocytes interconnected via V j -sensitive GJ channels.
Šnipas et al. (Sun,) studied this question.