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Dec 29, 2009

Scientists Suggest a Common Mechanism May be Responsible for Many Diseases of Excitability

  • The functional consequence of three inherited mutations in voltage-gated sodium channels have been determined by researchers from the Indiana University School of Medicine, Indianapolis. Their results suggest that there might be a common mechanism for many channelopathies—diseases arising from mutations in ion channel genes—though this mechanism was previously described to occur normally in only a few types of neurons.  

    The mutations under investigation have been associated with many different human disorders of excitability, including genetic forms of epilepsy, chronic pain, myotonia, and cardiac arrhythmias. The scientists published their findings online December 28 in The Journal of Clinical Investigation. The paper is titled “Human voltage-gated sodium channel mutations that cause inherited neuronal and muscle channelopathies increase resurgent sodium currents.”

    The authors sought to test the hypothesis that disease-causing mutations lead to increased resurgent currents—unusual sodium currents that have not previously been implicated in disorders of excitability. They studied the functional consequences of mutations in the human peripheral neuronal sodium channel Nav1.7, the human skeletal muscle sodium channel Nav1.4, and the human heart sodium channel Nav1.5, which are associated with an extreme pain disorder, a muscle condition characterized by slow relaxation of the muscles, and a heart condition and sudden infant death syndrome, respectively.  

    Expression of these mutated proteins in a rat-derived dorsal root ganglion neuronal system led to the conclusion that the mutations all altered the opening of the sodium channels such that the channels quickly reopened after an electrical impulse had been fired by the nerve cell. This caused a resurgent sodium current that triggered a second electrical impulse to be fired rapidly after the first.  

    The authors suggest that these observations are consistent with the diseases all being characterized by excitability. They say the results indicate that resurgent currents are associated with multiple channelopathies and are likely to be important contributors to neuronal and muscle disorders of excitability.

     



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