Evaluation of Small-Molecule Candidates as Modulators of M-Type K⁺ Currents: Impacts on Current Amplitude, Gating,...

The core subunits of the K_V7.2, K_V7.3, and K_V7.5 channels, encoded by the KCNQ2, KCNQ3, and KCNQ5 genes, are expressed across various cell types and play a key role in generating the M-type K⁺ current (I_K(M)). This current is characterized by an activation threshold at low voltages and displays slow activation and deactivation kinetics. Variations in the amplitude and gating kinetics of I_K(M) can significantly influence membrane excitability. Notably, I_K(M) demonstrates distinct voltage-dependent hysteresis when subjected to prolonged isosceles-triangular ramp pulses. In this review, we explore various small-molecule modulators that can either inhibit or enhance the amplitude of I_K(M), along with their perturbations on its gating kinetics and voltage-dependent hysteresis. The inhibitors of I_K(M) highlighted here include bisoprolol, brivaracetam, cannabidiol, nalbuphine, phenobarbital, and remdesivir. Conversely, compounds such as flupirtine, kynurenic acid, naringenin, QO-58, and solifenacin have been shown to enhance I_K(M). These modulators show potential as pharmacological or therapeutic strategies for treating certain disorders linked to gain-of-function or loss-of-function mutations in M-type K⁺ (K_V7x or KCNQx) channels.