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The Journal of Neuroscience, December 15, 1998, 18(24):10320-10334

Gating of the L-Type Ca Channel in Human Skeletal Myotubes: An Activation Defect Caused by the Hypokalemic Periodic Paralysis Mutation R528H

James A. Morrill¹, Robert H. Brown Jr³, and Stephen C. Cannon^{1, 2, 3}

¹ Program in Neuroscience, Division of Medical Sciences, and ² Department of Neurobiology, Harvard Medical School, and ³ Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts 02214

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.

Key words: dihydropyridine receptor; L-type calcium channel; human skeletal muscle; cultured cells; familial periodic paralysis; patch clamp

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Copyright © 1998 Society for Neuroscience  0270-6474/98/182410320-15$05.00/0

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