A CLCN1 mutation in dominant myotonia congenita impairs the increment of chloride conductance during repetitive depolarization

作者：Tsujino Akira^*; Kaibara Muneshige; Hayashi Hideki; Eguchi Hiroto; Nakayama Susumu; Sato Katsuya; Fukuda Taku; Tateishi Yohei; Shirabe Susumu; Taniyama Kohtaro; Kawakami Atsushi

来源：Neuroscience Letters, 2011, 494(2): 155-160.

DOI：10.1016/j.neulet.2011.03.002

• Myotonia congenita
• ClC-1
• Mutation
• Whole-cell recording
• Kinetics

Myotonia congenita is caused by mutation of the CLCN1 gene, which encodes the human skeletal muscle chloride channel (ClC-1). The ClC-1 protein is a dimer comprised of two identical subunits each incorporating its own separate pore. However, the precise pathophysiological mechanism underlying the abnormal ClC-1 channel gating in some mutants is not fully understood. We characterized a ClC-1 mutation, Pro-480-Thr (P480T) identified in dominant myotonia congenita, by using whole-cell recording. P480T ClC-1 revealed significantly slowed activation kinetics and a slight depolarizing shift in the voltage-dependence of the channel gating. Wild-type/mutant heterodimers exhibited similar kinetic properties and voltage-dependency to mutant homodimers. Simulating myotonic discharge with the voltage clamp protocol of a 50 Hz train pulse, the increment of chloride conductance was impaired in both wild-type/mutant heterodimers and mutant homodimers, clearly indicating a dominant-negative effect. Our data showed that slow activation gating of P480T ClC-1 impaired the increment of chloride conductance during repetitive depolarization, thereby accentuating the chloride conductance reduction caused by a slight depolarizing shift in the voltage-dependence of the channel gating. This pathophysiology may explain the clinical features of myotonia congenita.

• 出版日期2011-4-25