Kcnk2, also known as TREK1, is a member of the two-pore domain potassium (K2P) channel family. It is crucial for maintaining the resting membrane potential of cells, which is essential for normal cellular function. By controlling the potassium ion flow, it influences the excitability of neurons and other excitable cells. Kcnk2 has been associated with multiple biological pathways, and its function is vital in the central nervous system (CNS) [2,3,6]. Zebrafish, with their two orthologs kcnk2a and kcnk2b, serve as a useful in vivo research model to study Kcnk2-targeted strategies due to the similar biophysiological and pharmacological properties to human KCNK2 [7].

In esophageal squamous cell carcinoma (ESCC), miR-132-3p can bind to the 3'-untranslated region of Kcnk2 and inhibit its gene expression. Knockdown of Kcnk2 promotes ESCC progression in vitro, suggesting that Kcnk2 may act as a suppressor in ESCC [1]. In spinal cord ischemia-reperfusion injury, overexpression of Kcnk2 enhanced the viability and inhibited the apoptosis of hypoxia/reoxygenation-treated PC12 cells. The transcription factor Foxd3 activates miR-214, which targets Kcnk2, indicating a regulatory mechanism in this injury [4]. In pulmonary arterial hypertension, the up-regulated expression of Kcnk2 in pulmonary arterial smooth muscle cells (PASMCs) facilitates their proliferation and migration via enhanced Ca2+ signaling and JNK signaling pathway [5]. In the context of the blood-brain barrier (BBB), TREK1 (Kcnk2) was downregulated upon inflammation. Blocking of TREK1 increased lymphocyte migration, while activation had the opposite effect. In TREK1-deficient (Trek1 (-/-)) mice, brain endothelial cells displayed an inflammatory phenotype and leukocyte trafficking was facilitated, as demonstrated in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis [2].

In conclusion, Kcnk2 plays essential roles in maintaining cell membrane resting potential and influencing cell excitability. Model-based research, especially KO mouse models like in the study of BBB-related diseases, has revealed its significance in various disease conditions such as ESCC, spinal cord injury, and pulmonary arterial hypertension. Understanding Kcnk2's functions provides insights into the underlying mechanisms of these diseases, potentially guiding the development of new therapeutic strategies.

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. Le Guen, Yann, Philippe, Cathy, Riviere, Denis, Mangin, Jean-François, Frouin, Vincent. 2018. eQTL of KCNK2 regionally influences the brain sulcal widening: evidence from 15,597 UK Biobank participants with neuroimaging data. In Brain structure & function, 224, 847-857. doi:10.1007/s00429-018-1808-9. https://pubmed.ncbi.nlm.nih.gov/30519892/

7. Nasr, Nathalie, Faucherre, Adèle, Borsotto, Marc, Jopling, Chris, Moha Ou Maati, Hamid. 2018. Identification and characterization of two zebrafish Twik related potassium channels, Kcnk2a and Kcnk2b. In Scientific reports, 8, 15311. doi:10.1038/s41598-018-33664-9. https://pubmed.ncbi.nlm.nih.gov/30333618/