KCNG4, also known as Kv6.4, is a silent member of the voltage-gated potassium (Kv) channel superfamily. It forms heterotetramers with members of the KCNB (Kv2) family, and is involved in regulating the electrical activity of cells. Voltage-gated potassium channels play crucial roles in many biological processes, such as neuronal signaling, muscle contraction, and cell development [1,4,5]. Genetic models, like knockout mouse models, are valuable tools for studying its functions.

In a transgenic mouse model with targeted deletion of Kv6.4 (Kcng4-/-), male sterility was observed due to disturbed spermiogenesis, as indicated by a severe reduction in total sperm-cell count, absence of motile spermatozoa, and abnormal sperm morphology [6]. In zebrafish, different mutations in kcng4b (a related gene) affected the activity of the Kv channel and led to a range of ear development defects, such as failure of kinocilia to extend, formation of ectopic otoliths, or failure of otolith development [3]. Also, in human studies, a genetic variant Kv6.4-L360P linked to migraines almost completely abolishes Kv2 currents, potentially leading to migraine pathology in the trigeminal system [1]. In Hirschsprung's disease, KCNG4 gene expression was significantly downregulated in both aganglionic and ganglionic specimens compared to controls, suggesting its role in colonic motility [2].

In conclusion, KCNG4 plays essential roles in multiple biological processes. Model-based research, especially KO mouse models, has revealed its significance in male fertility, ear development, migraine pathogenesis, and colonic motility. Understanding KCNG4 functions can provide insights into the mechanisms of these associated diseases and potentially offer new therapeutic targets.

References:

1. Lacroix, Gabriel, Bhat, Shreyas, Shafia, Zerghona, Blunck, Rikard. 2024. KCNG4 Genetic Variant Linked to Migraine Prevents Expression of KCNB1. In International journal of molecular sciences, 25, . doi:10.3390/ijms25168960. https://pubmed.ncbi.nlm.nih.gov/39201645/

2. O'Donnell, Anne Marie, Nakamura, Hiroki, Tomuschat, Christian, Marayati, Naoum Fares, Puri, Prem. 2018. Altered expression of KCNG3 and KCNG4 in Hirschsprung's disease. In Pediatric surgery international, 35, 193-197. doi:10.1007/s00383-018-4394-2. https://pubmed.ncbi.nlm.nih.gov/30386900/

3. Jędrychowska, Justyna, Vardanyan, Vitya, Wieczor, Milosz, Kuznicki, Jacek, Korzh, Vladimir. 2024. Mutant analysis of Kcng4b reveals how the different functional states of the voltage-gated potassium channel regulate ear development. In Developmental biology, 513, 50-62. doi:10.1016/j.ydbio.2024.03.002. https://pubmed.ncbi.nlm.nih.gov/38492873/

4. Stewart, Robert G, Marquis, Matthew J, Jo, Sooyeon, Ferns, Michael, Sack, Jon T. 2025. A Kv2 inhibitor combination reveals native neuronal conductances consistent with Kv2/KvS heteromers. In bioRxiv : the preprint server for biology, , . doi:10.1101/2024.01.31.578214. https://pubmed.ncbi.nlm.nih.gov/38352561/

5. Jędrychowska, Justyna, Korzh, Vladimir. 2019. Kv2.1 voltage-gated potassium channels in developmental perspective. In Developmental dynamics : an official publication of the American Association of Anatomists, 248, 1180-1194. doi:10.1002/dvdy.114. https://pubmed.ncbi.nlm.nih.gov/31512327/

6. Regnier, Glenn, Bocksteins, Elke, Marei, Waleed F, Leroy, Jo L M R, Snyders, Dirk J. . Targeted deletion of the Kv6.4 subunit causes male sterility due to disturbed spermiogenesis. In Reproduction, fertility, and development, 29, 1567-1575. doi:10.1071/RD16075. https://pubmed.ncbi.nlm.nih.gov/27677211/