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

The core subunits of the K7.2, K7.3, and K7.5 channels, encoded by the , , and genes, are expressed across various cell types and play a key role in generating the M-type K current (). 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 can significantly influence membrane excitability. Notably, 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 , along with their perturbations on its gating kinetics and voltage-dependent hysteresis. The inhibitors of 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 . 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 (K7x or ) channels.