AN ASPARTIC-ACID RESIDUE IMPORTANT FOR VOLTAGE-DEPENDENT GATING OF HUMAN MUSCLE CHLORIDE CHANNELS

A point mutation (D136G) predicting the substitution of glycine for as partate in position 136 of the human muscle Cl- channel (hCIC-1) cause s recessive generalized myotonia. Heterologous expression of a recombi nant D136G produces functional Cl- channels with profound alterations in voltage-dependent gating, without concomitant changes in pore prope rties. The mutant exhibits slowly activating current upon hyperpolariz ation, in contrast to wild-type channels, which display time-dependent current decay (deactivation) at negative membrane potentials. Steady- state activation of D136G depends upon the transmembrane Cl- gradient, reaching zero at voltages positive to the Cl- reversal potential in p hysiological Cl- distribution. This explains the reduced sarcolemmal C l- conductance that causes myotonia. The functional disturbances exhib ited by D136G may stem from a defect in the CIC-1 voltage sensor.