Gating of the L-type Ca channel in human skeletal myotubes: An activation defect caused by the hypokalemic periodic paralysis mutation R528H

The skeletal muscle L-type Ca channel serves a dual role as a calcium-condu cting pore and as the voltage sensor coupling t-tubule depolarization to ca lcium release from the sarcoplasmic reticulum. Mutations in this channel ca use hypokalemic periodic paralysis (HypoPP), a human autosomal dominant dis order characterized by episodic failure of muscle excitability that occurs in association with a decrease in serum potassium. The voltage-dependent ga ting of L-type Ca channels was characterized by recording whole-cell Ca cur rents in myotubes cultured from three normal individuals and from a patient carrying the HypoPP mutation R528H. We found two effects of the R528H muta tion on the L-type Ca current in HypoPP myotubes: (1) a mild reduction in c urrent density and (2) a significant slowing of the rate of activation. We also measured the voltage dependence of steady-state L-type Ca current inac tivation and characterized, for the first time in a mammalian preparation, the kinetics of both entry into and recovery from inactivation over a wide range of voltages. The R528H mutation had no effect on the kinetics or volt age dependence of inactivation.