Voltage‐sensor mutations in channelopathies of skeletal muscle

SC Cannon - The Journal of physiology, 2010 - Wiley Online Library
The Journal of physiology, 2010Wiley Online Library
Mutations of voltage‐gated ion channels cause several channelopathies of skeletal muscle,
which present clinically with myotonia, periodic paralysis, or a combination of both.
Expression studies have revealed both loss‐of‐function and gain‐of‐function defects for the
currents passed by mutant channels. In many cases, these functional changes could be
mechanistically linked to the defects of fibre excitability underlying myotonia or periodic
paralysis. One remaining enigma was the basis for depolarization‐induced weakness in …
Mutations of voltage‐gated ion channels cause several channelopathies of skeletal muscle, which present clinically with myotonia, periodic paralysis, or a combination of both. Expression studies have revealed both loss‐of‐function and gain‐of‐function defects for the currents passed by mutant channels. In many cases, these functional changes could be mechanistically linked to the defects of fibre excitability underlying myotonia or periodic paralysis. One remaining enigma was the basis for depolarization‐induced weakness in hypokalaemic periodic paralysis (HypoPP) arising from mutations in either sodium or calcium channels. Curiously, 14 of 15 HypoPP mutations are at arginines in S4 voltage sensors, and recent observations show that these substitutions support an alternative pathway for ion conduction, the gating pore, that may be the source of the aberrant depolarization during an attack of paralysis.
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