Kcnj2, which encodes the α subunit of the K+ channel protein Kir2.1, is a gene associated with the inwardly rectifying potassium channel. This channel is involved in regulating cell membrane potential, influencing processes like electrical activity in neurons and cardiomyocytes [3]. It has significant biological importance in maintaining normal physiological functions in the body, and genetic models can be valuable for studying its functions.

In a human brain organoid model of traumatic brain injury, genome-wide CRISPR interference screening identified that inhibition of Kcnj2 potently mitigated neurodegenerative processes both in vitro and in vivo, including in organoids derived from C9ORF72 amyotrophic lateral sclerosis/frontotemporal dementia patients [1]. In Andersen-Tawil Syndrome (ATS), loss-of-function mutations in Kcnj2 are the cause in approximately 50-60% of cases. ATS is characterized by periodic muscle paralysis, cardiac arrhythmia, and physical developmental dysmorphisms [3,4,5]. In osteosarcoma, Kcnj2 is overexpressed in advanced-stage tissues and cells with high metastatic potential. Inhibition of Kcnj2 repressed the metastasis of osteosarcoma cells [2]. In the context of atrial fibrillation, knockout of spexin increased AF susceptibility in mice, along with upregulation of Kcnj2 in the atrium, increased IK1 current, and impaired Ca2+ handling [6].

In summary, Kcnj2 plays a crucial role in maintaining normal physiological functions, especially in the context of neural, cardiac, and muscular activities. Model-based research, such as gene knockout and interference studies, has revealed its significance in neurodegenerative diseases, genetic channelopathies like ATS, cancer metastasis, and atrial fibrillation. Understanding Kcnj2's functions through these models provides insights into disease mechanisms and potential therapeutic targets for these conditions.

References:

1. Lai, Jesse D, Berlind, Joshua E, Fricklas, Gabriella, Zhao, Zhen, Ichida, Justin K. . KCNJ2 inhibition mitigates mechanical injury in a human brain organoid model of traumatic brain injury. In Cell stem cell, 31, 519-536.e8. doi:10.1016/j.stem.2024.03.004. https://pubmed.ncbi.nlm.nih.gov/38579683/

2. Shen, Mao, Pan, Runsang, Lei, Shan, Nie, Yingjie, Tian, Xiaobin. 2023. KCNJ2/HIF1α positive-feedback loop promotes the metastasis of osteosarcoma. In Cell communication and signaling : CCS, 21, 46. doi:10.1186/s12964-023-01064-w. https://pubmed.ncbi.nlm.nih.gov/36864422/

3. Pérez-Riera, Andrés Ricardo, Barbosa-Barros, Raimundo, Samesina, Nelson, Nikus, Kjell, Brugada, Pedro. . Andersen-Tawil Syndrome: A Comprehensive Review. In Cardiology in review, 29, 165-177. doi:10.1097/CRD.0000000000000326. https://pubmed.ncbi.nlm.nih.gov/32947483/

4. Goslinga, Jill A, PtáČek, Louis J, Tawil, Rabi, Fay, Alexander. . Andersen-Tawil syndrome. In Handbook of clinical neurology, 203, 59-67. doi:10.1016/B978-0-323-90820-7.00001-X. https://pubmed.ncbi.nlm.nih.gov/39174254/

5. Le Tanno, Pauline, Folacci, Mathilde, Revilloud, Jean, Roux-Buisson, Nathalie, Fauré, Julien. 2021. Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome. In Frontiers in genetics, 12, 773177. doi:10.3389/fgene.2021.773177. https://pubmed.ncbi.nlm.nih.gov/34899860/

6. Li, Desheng, Liu, Yang, Li, Changzhu, Li, Yue, Pan, Zhenwei. 2024. Spexin Diminishes Atrial Fibrillation Vulnerability by Acting on Galanin Receptor 2. In Circulation, 150, 111-127. doi:10.1161/CIRCULATIONAHA.123.067517. https://pubmed.ncbi.nlm.nih.gov/38726666/