FUNCTIONAL CONSEQUENCES OF A NA+ CHANNEL MUTATION CAUSING HYPERKALEMIC PERIODIC PARALYSIS

Hyperkalemic periodic paralysis (HYPP), one of several inheritable myo tonic diseases, results from genetic defects in the human skeletal mus cle Na+ channel. In some pedigrees, HYPP is correlated with a single b ase pair substitution resulting in a Met replacing Thr704 in the fifth transmembrane segment of the second domain. This region is totally co nserved between the human and rat channels. We have introduced the hum an mutation into the corresponding region of the rat muscle Na+ channe l cDNA and expressed it in human embryonic kidney 293 cells. Patch-cla mp recordings show that this mutation shifts the voltage dependence of activation by 10-15 mV in the negative direction. The shift results i n a persistent Na+ current that activates near -70 mV; this phenomenon could underlie the abnormal muscle activity observed in patients with HYPP.