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Original article (peer-reviewed)

Journal Acta Physiologica
Volume (Issue) 227(S719)
Page(s) OS 03-08
Title of proceedings Acta Physiologica
DOI 10.1111/apha.v227.s719

Open Access

URL https://onlinelibrary.wiley.com/doi/epdf/10.1111/apha.13383
Type of Open Access Publisher (Gold Open Access)

Abstract

Background: Mutations of the cardiac Na+ channel can cause arrhythmogenic syndromes. Many of these mutations exert a dominant-negative effect even if both wild type and mutant channels are trafficked to the membrane. Recent molecular studies showed that Na+ channels form dimers linked by a protein called 14-3-3 and patch clamp experiments indicate that this link causes coupled gating and synchronization of openings and closings. This leads to the hypotheses that Na+ channel function is modulated by allosteric interactions between channels and that these interactions may contribute to the negative dominance of certain mutations. Methods: A modelling paradigm was developed in which pairs of interacting Na+ channels are considered as the functional units underlying the Na+ current. Markovian models of two channels are combined together and allosteric interactions are incorporated by modifying the free energies of the combined states and/or barriers between states, which preserves microscopic reversibility. Systematic simulations permit to investigate how specific interactions affect the behaviour of the Na+ current at the single channel and ensemble average levels. Results: Simulations using two 2-state models (C-O, closed-open) revealed that increasing the free energy of the compound states CO/OC (one channel closed, the other open) synchronizes the openings and closings. This energy can be regarded as potential energy accumulated in the linker protein. Simulations using two 3-state models (closed-open-inactivated) revealed that synchronization of both openings and closings must also involve interactions between further compound states. Using two 6-state Na+ channel models, previously reported experimental results could be replicated mainly by increasing the free energies of the CO/OC states and lowering the energy barriers between the CO/OC and the CO/OO states. The Na+ channel model was then modified to simulate a negative dominant Nav1.5 mutation (L325R). Simulations of homodimers vs. heterodimers in the presence vs. absence of interactions showed that the latter impair the opening of the wild-type channel and thus contribute to negative dominance. Conclusions: This new modeling framework is an invaluable tool to understand the interactions between ion channels and to identify interaction mechanisms based on experimental observations. Allosteric interactions between cardiac Na+ channels may contribute to the negative dominance of certain mutations.
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