Kcnmb1-KO Mouse

KCNMB1, encoding the β1 subunit of the large-conductance calcium-activated potassium (BK) channel, is crucial for regulating BK channel function. The BK channels are involved in various physiological processes, such as controlling smooth muscle contraction, neurotransmitter release, and maintaining vascular flexibility [3,4,6].

In a meta-analysis, the dominant model of KCNMB1 E65K polymorphism was significantly associated with essential hypertension risk in Asian population, suggesting its potential role in hypertension-related genetic susceptibility [1]. In the context of pulmonary fibrosis, fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) show increased KCNMB1 expression, which corresponds to enhanced BK channel activity. Knockdown of KCNMB1 attenuates the ability of fibroblasts to differentiate into myofibroblasts, highlighting its role in fibrotic disorders [2]. In atherosclerotic blood vessels, 7-ketocholesterol, an atherogenic factor, down-regulates KCNMB1 through the aryl hydrocarbon receptor (AhR) pathway, potentially contributing to vascular rigidity and hypertension [4]. Mice lacking Kcnmb1 (Kcnmb1-/-) are hypertensive, volume expanded, and have reduced urinary K and Na clearances. The hypertension in these mice is mainly due to aldosteronism resulting from renal potassium retention and hyperkalemia, indicating a renal origin of the hypertension phenotype [5].

In conclusion, KCNMB1 plays essential roles in multiple biological processes and disease conditions. Studies using gene-knockout mouse models, like the Kcnmb1-/-mice, have revealed its significant contributions to hypertension, pulmonary fibrosis, and atherosclerosis-related pathophysiological mechanisms. These findings provide valuable insights into understanding the underlying molecular mechanisms of these diseases and may potentially guide the development of novel therapeutic strategies.

References:

1. Zhancheng, Wang, Wenhui, Ji, Yun, Jiang, Yan, Shen, Jin, Li. . The dominant models of KCNJ11 E23K and KCNMB1 E65K are associated with essential hypertension (EH) in Asian: Evidence from a meta-analysis. In Medicine, 98, e15828. doi:10.1097/MD.0000000000015828. https://pubmed.ncbi.nlm.nih.gov/31169684/

2. Scruggs, Anne M, Grabauskas, Gintautas, Huang, Steven K. . The Role of KCNMB1 and BK Channels in Myofibroblast Differentiation and Pulmonary Fibrosis. In American journal of respiratory cell and molecular biology, 62, 191-203. doi:10.1165/rcmb.2019-0163OC. https://pubmed.ncbi.nlm.nih.gov/31486669/

3. Bukiya, Anna N, Leo, M Dennis, Jaggar, Jonathan H, Dopico, Alex M. 2021. Cholesterol activates BK channels by increasing KCNMB1 protein levels in the plasmalemma. In The Journal of biological chemistry, 296, 100381. doi:10.1016/j.jbc.2021.100381. https://pubmed.ncbi.nlm.nih.gov/33556372/

4. Son, Yonghae, Chun, Wonjoo, Ahn, Yong-Tae, Lee, Chu, An, Won G. 2015. 7-Ketocholesterol induces the reduction of KCNMB1 in atherosclerotic blood vessels. In Biochemical and biophysical research communications, 457, 324-7. doi:10.1016/j.bbrc.2014.12.109. https://pubmed.ncbi.nlm.nih.gov/25576871/

5. Grimm, P Richard, Irsik, Debra L, Settles, Deann C, Holtzclaw, J David, Sansom, Steven C. 2009. Hypertension of Kcnmb1-/- is linked to deficient K secretion and aldosteronism. In Proceedings of the National Academy of Sciences of the United States of America, 106, 11800-5. doi:10.1073/pnas.0904635106. https://pubmed.ncbi.nlm.nih.gov/19556540/

6. Toro, B, Cox, N, Wilson, R J, Toro, L, Zarei, M M. 2006. KCNMB1 regulates surface expression of a voltage and Ca2+-activated K+ channel via endocytic trafficking signals. In Neuroscience, 142, 661-9. doi:. https://pubmed.ncbi.nlm.nih.gov/16908104/