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Functional consequences of a Na+ channel mutation causing hyperkalemic periodic paralysis
T R Cummins1, J Zhou, F J Sigworth
1Interdepartmental Neuroscience Program, Yale University School of Medicine, New Haven, Connecticut 06510.
Neuron
|April 1, 1993
Summary
Genetic defects in the skeletal muscle sodium channel cause Hyperkalemic Periodic Paralysis (HYPP). A specific mutation causes abnormal muscle activity by creating a persistent sodium current.
Area of Science:
- Molecular Biology
- Neuroscience
- Genetics
Background:
- Hyperkalemic Periodic Paralysis (HYPP) is an inheritable myotonic disease.
- Genetic defects in the skeletal muscle sodium channel are implicated in HYPP.
Purpose of the Study:
- To investigate the functional consequences of a specific HYPP-associated mutation in the skeletal muscle sodium channel.
- To elucidate the molecular mechanisms underlying abnormal muscle activity in HYPP patients.
Main Methods:
- Introduced a human HYPP mutation (Met replacing Thr704) into rat muscle Na+ channel cDNA.
- Expressed the mutated channel in human embryonic kidney 293 cells.
- Utilized patch-clamp recordings to analyze channel function.
Main Results:
- The Thr704Met mutation shifted the voltage dependence of activation by 10-15 mV in the negative direction.
- This shift resulted in a persistent Na+ current activating near -70 mV.
- The observed channel behavior provides a potential explanation for HYPP's abnormal muscle activity.
Conclusions:
- The identified mutation in the skeletal muscle sodium channel is sufficient to cause a persistent Na+ current.
- This persistent current is a likely mechanism underlying the pathophysiology of Hyperkalemic Periodic Paralysis.