Voltage-gated K V 7 (KCNQ) potassium (K + ) channels are composed of five subtypes (K V 7.1-K V 7.5) and significantly contribute to the regulation of action potential firing and frequency in various cell types in the central and peripheral nervous systems. Among them, K V 7.2/K V 7.3 heteromeric channels are primarily responsible for generating the M-current (I M ) and regulating neuronal excitability. Therefore, these channels represent key therapeutic targets for treatment of epilepsy patients, such as those with epileptic encephalopathy (EE). Experimental studies using atomic force microscopy (AFM) show that when cells express KCNQ2 (K V 7.2) and KCNQ3 (K V 7.3) in roughly equal amounts, the resulting heterotetramers assemble predominantly as 2:2 complexes with random subunit configurations. However, varying the DNA ratio of the two subunits revealed that stoichiometry is flexible, and subunit arrangement is unconstrained. It remains unclear if any molecular or thermodynamic properties influence the assembly or if they impact channel viability. Thus, we set out to investigate which stoichiometries and arrangements are most energetically favorable. Here, we provide an atomistic perspective on the underlying dynamics and molecular determinants of K V 7.2/K V 7.3 heteromeric channels, using homology modeling and molecular dynamics simulations. We examine how subunit arrangements, PIP 2 interactions, and calmodulin (CaM/Ca 2+ ) binding influence channel stability and function. These models offer mechanistic insight into how pathogenic KCNQ2/KCNQ3 mutations might disrupt channel behavior and facilitate our ongoing efforts to discover rational therapeutic solutions for treatment-resistant pathologies such as EE.
Sk et al. (Sun,) studied this question.