Kcnj10, also known as Kir4.1 or Kir1.2, encodes an ATP-sensitive inwardly-rectifying potassium channel. It is expressed in various tissues such as the brain, inner ear, and kidney. In the kidney, it participates in K⁺ recycling and generating negative membrane potential in specific nephron segments, and is involved in regulating the Na-Cl cotransporter through the Cl⁻-sensitive with-no-lysine kinase-SPAK pathway [3]. In the cochlea, it is critical for the generation of the endocochlear potential [5]. In the brain, it is involved in regulating neuronal excitability [4].

In a collecting system-specific Kcnj10-knockout mouse model (AQP2cre:Kcnj10flox/flox), the knockout mice showed higher kaliuresis and lower plasma potassium than control mice when treated with thiazide diuretics or on a potassium-restricted diet. This indicates that Kcnj10 in the collecting system contributes to the renal control of potassium homeostasis by regulating the epithelial sodium channel (ENaC) and the renal outer medullary potassium channel (ROMK) [6]. Heterozygous conditional knockout of Kcnj10 in the cerebellum of mice led to dystonic posture, poor motor coordination, and increased firing rate of deep cerebellar nuclei, suggesting its role in paroxysmal kinesigenic dyskinesia (PKD) [1,2].

In conclusion, Kcnj10 plays essential roles in potassium homeostasis in the kidney, endocochlear potential generation in the inner ear, and regulation of neuronal excitability in the brain. The gene knockout and conditional knockout mouse models have significantly contributed to understanding its functions in diseases such as PKD and renal potassium-related disorders.

References:

1. Huang, Xiaojun, Fu, Xin, Wu, Jingying, Tong, Xiaoping, Cao, Li. 2024. Heterozygous KCNJ10 Variants Affecting Kir4.1 Channel Cause Paroxysmal Kinesigenic Dyskinesia. In Movement disorders : official journal of the Movement Disorder Society, 39, 2199-2210. doi:10.1002/mds.30025. https://pubmed.ncbi.nlm.nih.gov/39367724/

2. Li, Yun-Lu, Lin, Jingjing, Huang, Xuejing, Xiong, Zhi-Qi, Chen, Wan-Jin. 2024. Heterozygous Variants in KCNJ10 Cause Paroxysmal Kinesigenic Dyskinesia Via Haploinsufficiency. In Annals of neurology, 96, 758-773. doi:10.1002/ana.27018. https://pubmed.ncbi.nlm.nih.gov/38979912/

3. Su, Xiao-Tong, Wang, Wen-Hui. 2016. The expression, regulation, and function of Kir4.1 (Kcnj10) in the mammalian kidney. In American journal of physiology. Renal physiology, 311, F12-5. doi:10.1152/ajprenal.00112.2016. https://pubmed.ncbi.nlm.nih.gov/27122539/

4. Cui, Yihui, Yang, Yan, Ni, Zheyi, Wu, Shengxi, Hu, Hailan. . Astroglial Kir4.1 in the lateral habenula drives neuronal bursts in depression. In Nature, 554, 323-327. doi:10.1038/nature25752. https://pubmed.ncbi.nlm.nih.gov/29446379/

5. Strepay, Dillon, Olszewski, Rafal T, Nixon, Sydney, Roux, Isabelle, Hoa, Michael. 2023. Transgenic Tg(Kcnj10-ZsGreen) Fluorescent Reporter Mice Allow Visualization of Intermediate Cells in the Stria Vascularis. In Research square, , . doi:10.21203/rs.3.rs-3393161/v1. https://pubmed.ncbi.nlm.nih.gov/37886521/

6. Penton, David, Vohra, Twinkle, Banki, Eszter, Warth, Richard, Loffing, Johannes. 2020. Collecting system-specific deletion of Kcnj10 predisposes for thiazide- and low-potassium diet-induced hypokalemia. In Kidney international, 97, 1208-1218. doi:10.1016/j.kint.2019.12.016. https://pubmed.ncbi.nlm.nih.gov/32299681/