Kcnk2, also known as TWIK-related potassium channel-1 (TREK1), is a member of the two-pore domain potassium (K2P) channel family. It is essential for maintaining cellular membrane resting potentials, regulating membrane excitability, and plays a role in processes like controlling the transition of cells and molecules into the CNS [2]. Phosphorylation of Kcnk2 can reversibly convert a hippocampal potassium leak into a voltage-dependent channel, revealing a dynamic regulation pathway of excitability [3].

In esophageal squamous cell carcinoma (ESCC), miR-132-3p can bind to the 3'-untranslated region of Kcnk2 and inhibit its expression, promoting ESCC progression [1]. In spinal cord ischemia-reperfusion injury, Foxd3 activates miR-214 which targets Kcnk2, and overexpression of Kcnk2 enhances cell viability and inhibits apoptosis [4]. In pulmonary arterial hypertension, up-regulated expression of Kcnk2 facilitates the proliferation and migration of pulmonary arterial smooth muscle cells via enhanced Ca2+ and JNK signaling pathways [5]. Also, genetic variations in Kcnk2 are associated with major depressive disorder and response to antidepressant treatment [6,7].

In summary, Kcnk2 is crucial for maintaining membrane resting potential and regulating excitability. Studies using various models, though not specifically KO/CKO mouse models in all cases, have revealed its significance in diseases such as ESCC, spinal cord injury, pulmonary arterial hypertension, and major depressive disorder. Understanding Kcnk2's function provides insights into the mechanisms of these diseases and potential therapeutic targets.

References:

1. Wang, Jing, Li, Jiaqiong, Cheng, Dan, Li, Xiang, Dong, Zigang. 2023. miR-132-3p promotes heat stimulation-induced esophageal squamous cell carcinoma tumorigenesis by targeting KCNK2. In Molecular carcinogenesis, 62, 583-597. doi:10.1002/mc.23504. https://pubmed.ncbi.nlm.nih.gov/37014157/

2. Bittner, Stefan, Ruck, Tobias, Fernández-Orth, Juncal, Meuth, Sven G. 2014. TREK-king the blood-brain-barrier. In Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology, 9, 293-301. doi:10.1007/s11481-014-9530-8. https://pubmed.ncbi.nlm.nih.gov/24557892/

3. Bockenhauer, D, Zilberberg, N, Goldstein, S A. . KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel. In Nature neuroscience, 4, 486-91. doi:. https://pubmed.ncbi.nlm.nih.gov/11319556/

4. Li, Ran, Zhao, Kunchi, Ruan, Qing, Meng, Chunyang, Yin, Fei. 2020. The transcription factor Foxd3 induces spinal cord ischemia-reperfusion injury by potentiating microRNA-214-dependent inhibition of Kcnk2. In Experimental & molecular medicine, 52, 118-129. doi:10.1038/s12276-019-0370-8. https://pubmed.ncbi.nlm.nih.gov/31959866/

5. Shima, Natsumi, Yamamura, Aya, Fujiwara, Moe, Suzuki, Yoshiaki, Yamamura, Hisao. 2024. Up-regulated expression of two-pore domain K+ channels, KCNK1 and KCNK2, is involved in the proliferation and migration of pulmonary arterial smooth muscle cells in pulmonary arterial hypertension. In Frontiers in cardiovascular medicine, 11, 1343804. doi:10.3389/fcvm.2024.1343804. https://pubmed.ncbi.nlm.nih.gov/38410243/

6. Congiu, Chiara, Minelli, Alessandra, Bonvicini, Cristian, Segala, Matilde, Gennarelli, Massimo. 2014. The role of the potassium channel gene KCNK2 in major depressive disorder. In Psychiatry research, 225, 489-92. doi:10.1016/j.psychres.2014.11.061. https://pubmed.ncbi.nlm.nih.gov/25535009/

7. Liou, Ying-Jay, Chen, Tai-Jui, Tsai, Shih-Jen, Cheng, Chih-Ya, Hong, Chen-Jee. . Support for the involvement of the KCNK2 gene in major depressive disorder and response to antidepressant treatment. In Pharmacogenetics and genomics, 19, 735-41. doi:10.1097/FPC.0b013e32832cbe61. https://pubmed.ncbi.nlm.nih.gov/19741570/