Potassium- sensitive loss of muscle force in the setting of reduced inward rectifier K+ current: Implications for Andersen-Tawil syndrome

• 成果类型: Article
• 署名作者: Elia, Nathaniel; Quinonez, Marbella; Wu, Fenfen; Mokhonova, Ekaterina; DiFranco, Marino; Spencer, Melissa J.; Cannon, Stephen C.
• 署名单位: University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-10364
• DOI: 10.1073/pnas.2418021122
• 发表日期: 2025-04-01
• 关键词: mammalian skeletal-muscle; hypokalemic periodic paralysis; mouse model; channel; kir2.1; channelopathies; depolarization; inactivation; variability; mutations

摘要

Andersen-Tawil syndrome (ATS) is an ion channelopathy with variable penetrance for the triad of periodic paralysis, arrhythmia, and dysmorphia. Dominant-negative mutations of KCNJ2 encoding the Kir2.1 potassium channel subunit are found in 60% of ATS families. As with most channelopathies, episodic attacks in ATS are frequently triggered by environmental stresses: exercise for periodic paralysis or stress with adrenergic stimulation for arrhythmia. Fluctuations in K+, either low or high, are potent triggers for attacks of weakness in other variants of periodic paralysis (hypokalemic periodic paralysis or hyperkalemic periodic paralysis). For ATS, the [K+] dependence is less clear; with reports describing weakness in high-K+ or low-K+. Patient trials with controlled K+ challenges are not possible, due to arrhythmias. We have developed two mouse models (genetic and pharmacologic) with reduced Kir currents, to address the question of K+-sensitive loss of force. These animal models and computational simulations both show K+-dependent weakness occurs only when Kir current is <30% of wildtype. As the Kir deficit becomes more severe, the phenotype shifts from high-K+-induced weakness to a combination where either high-K+ or low-K+ triggers weakness. A K+ channel agonist, retigabine, protects muscle from K+-sensitive weakness in our mouse models of the skeletal muscle involvement in ATS.