Voltage-gated Potassium Channels (Kv7): Molecular Structure, Regulation, and Role in Pathogenesis
Abstract
The potassium channels of the Kv7 family, comprising KCNQ1 to KCNQ5, assume a critical role in the regulation of membrane potential and cellular excitability within the nervous, cardiovascular, sensory, and endocrine systems. Their specificity to distinct tissues makes them associated with a wide range of pathological conditions, including epileptic encephalopathy, long QT syndrome, hearing impairment, and diabetes mellitus. The intricate molecular mechanisms regulating Kv7 channel function-including interactions with phosphatidylinositol 4,5-bisphosphate (PIP₂), calmodulin, and receptor-mediated signaling pathways-make these channels a key target for research in neuropharmacology and precision medicine.This review presents a comprehensive analysis of publications selected using specific keywords in international bibliographic databases (PubMed, Scopus, Web of Science, Google Scholar, and ScienceDirect) and specialized bioinformatics resources (PDB, UniProt, and AlphaFold). The focus is on research published between 2000 and 2025, with a particular emphasis on the past five years' findings. The final sample includes 128 original, peer-reviewed studies that meet criteria for scientific validity, innovation, and significance.The analysis uncovered the fundamental principles governing the regulation of Kv7 channels, encompassing lipid interactions, calcium-dependent modulation, and allosteric effects. Variations were observed among the Kv7.1-Kv7.5 isoforms in terms of their kinetics, the structure of the PIP₂-binding site, and susceptibility to pathological mutations. The Kv7.2/3 channels, which play a role in the generation of the M-current and the development of epilepsy, were examined in greater detail. Recent cryo-EM structural data were examined, along with preclinical and experimental efforts to pharmacologically modulate these channels using retigabine, ICA-069673, ZK-21, and novel derivatives. Consideration was given to the issue of tissue selectivity and the functional variability of pharmacological responses in the context of different mutations.The Kv7 ion channels constitute a sophisticated system that responds to stimuli from ions, lipids, and proteins. This intricate network enables precise regulation of neuronal activity and the maintenance of delicate balance.Recent breakthroughs in structural biology, genetic research, and electrophysiological studies have laid the groundwork for the development of targeted therapeutic approaches. However, there are still unanswered questions regarding the specific characteristics of various tissue types, the impact of post-translational modifications, and the consequences of mutations. Addressing these issues necessitates continued collaborative efforts to fully comprehend the intricate mechanisms underlying these phenomena.