Modeling the Interactions Between Sodium Channels Provides Insight Into the Negative Dominance of Certain Channel...

Na_v1.5 cardiac Na⁺ channel mutations can cause arrhythmogenic syndromes. Some of these mutations exert a dominant negative effect on wild-type channels. Recent studies showed that Na⁺ channels can dimerize, allowing coupled gating. This leads to the hypothesis that allosteric interactions between Na⁺ channels modulate their function and that these interactions may contribute to the negative dominance of certain mutations.

To investigate how allosteric interactions affect microscopic and macroscopic channel function, we developed a modeling paradigm in which Markovian models of two channels are combined. Allosteric interactions are incorporated by modifying the free energies of the composite states and/or barriers between states.

Simulations using two generic 2-state models (C-O, closed-open) revealed that increasing the free energy of the composite states CO/OC leads to coupled gating. Simulations using two 3-state models (closed-open-inactivated) revealed that coupled closings must also involve interactions between further composite states. Using two 6-state cardiac Na⁺ channel models, we replicated previous experimental results mainly by increasing the energies of the CO/OC states and lowering the energy barriers between the CO/OC and the CO/OO states. The channel model was then modified to simulate a negative dominant mutation (Na_v1.5 p.L325R). Simulations of homodimers and heterodimers in the presence and absence of interactions showed that the interactions with the variant channel impair the opening of the wild-type channel and thus contribute to negative dominance.

Our new modeling framework recapitulates qualitatively previous experimental observations and helps identifying possible interaction mechanisms between ion channels.