title: Gating of the L-type Ca channel in human skeletal myotubes: an activation defect caused by the hypokalemic periodic paralysis mutation R528H.
abstract: The skeletal muscle L-type Ca channel serves a dual role as a calcium-conducting pore and as the voltage sensor coupling t-tubule depolarization to calcium release from the sarcoplasmic reticulum. Mutations in this channel cause hypokalemic periodic paralysis (HypoPP), a human autosomal dominant disorder characterized by episodic failure of muscle excitability that occurs in association with a decrease in serum potassium. The voltage-dependent gating of L-type Ca channels was characterized by recording whole-cell Ca currents in myotubes cultured from three normal individuals and from a patient carrying the HypoPP mutation R528H. We found two effects of the R528H mutation on the L-type Ca current in HypoPP myotubes: (1) a mild reduction in current density and (2) a significant slowing of the rate of activation. We also measured the voltage dependence of steady-state L-type Ca current inactivation 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 voltage dependence of inactivation.
authors.affiliation: Program in Neuroscience, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts 02214, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Morrill
authors.forename: R H
authors.initials: RH
authors.lastname: Brown
authors.forename: S C
authors.initials: SC
authors.lastname: Cannon
mesh_terms: D001692:Biological Transport / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000235:genetics / Q000502:physiology*; D020746:Calcium Channels, L-Type; D002478:Cells, Cultured; D006801:Humans; D015640:Ion Channel Gating / Q000502:physiology*; D007700:Kinetics; D009124:Muscle Proteins / Q000235:genetics / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation; D010245:Paralyses, Familial Periodic / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D009124:Muscle Proteins; D002118:Calcium