MOLECULAR-BASIS FOR DECREASED MUSCLE CHLORIDE CONDUCTANCE IN THE MYOTONIC GOAT

Certain forms of myotonia, a condition characterized by delayed relaxa tion of muscle secondary to sarcolemmal hyperexcitability, are caused by diminished chloride conductance in the muscle cell membrane, We hav e investigated the molecular basis for decreased muscle chloride condu ctance in the myotonic goat, an historically important animal model fo r the elucidation of the role of chloride in muscle excitation, A sing le nucleotide change causing the substitution of proline for a conserv ed alanine residue in the carboxyl terminus of the goat muscle chlorid e channel (gClC-1) was discovered, Heterologous expression of the muta tion demonstrated a substantial (+47 mV) shift in the midpoint of stea dy-state activation of the channel, resulting in a diminished channel open probability at voltages near the resting membrane potential of sk eletal muscle, These results provide a molecular basis for the decreas ed chloride conductance in myotonic muscle.