Novel Approaches to Therapy of Muscle Ion Channelopathies

Wright State University, Dayton OH

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Abstract

We will study mouse models of two muscle diseases with abnormal electrical activity. In myotonia congenita, hyperexcitability is caused by loss of function mutations in the muscle ClC- 1 chloride channel (an anti-excitability subthreshold current). Myotonia (muscle stiffness) is caused by unwanted firing of action potentials. Hyperkalemic periodic paralysis (HPP) is caused by gain of function mutations in the muscle Nav1.4 sodium channel, which increase a non- inactivating Na current (Na persistent or NaP). Patients with HPP suffer from both myotonia and attacks of weakness caused by depolarization of muscle by NaP, which inactivates the Na current responsible for action potentials (Na transient current, NaT). We will determine whether block of NaP rather than NaT is the mechanism underlying efficacy of Na channel blockers in treating myotonia congenita. We will use a genetic, a pharmacologic and a computer model of myotonia congenita to examine the roles of NaP and NaT in triggering hyperexcitability. We will also determine whether selective block of NaP provides effective therapy for hyperkalemic periodic paralysis (HPP). Na channel blockers have surprisingly been ineffective in treating HPP. We hypothesize treatment failed because the blockers used were not selective for NaP so block of NaT worsened weakness. If we are correct that NaP regulates excitability, it would suggest the approach to developing new Na channel blockers needs to be fundamentally altered. Instead of identifying drugs which block NaT, the goal would be to identify drugs which block NaP, but do not block NaT. Development of selective blockers of NaP could improve therapy of muscle channelopathies, cardiac arrhythmias, epilepsy and neuropathic pain.