title: Enhanced inactivation and pH sensitivity of Na(+) channel mutations causing hypokalaemic periodic paralysis type II.
abstract: Hypokalaemic periodic paralysis (hypoPP) is a dominantly inherited muscle disorder characterized by episodes of flaccid weakness. Previous genetic studies revealed mutations in the voltage-gated calcium channel alpha1-subunit (CACNA1S gene) in families with hypoPP (type I). Electrophysiological studies on these mutants in different expression systems could not explain the pathophysiology of the disease. In addition, several mutations (Arg669His, Arg672His, Arg672Gly and Arg672Ser) in the voltage sensor of the skeletal muscle sodium channel alpha-subunit (SCN4A gene) have been found in families with hypoPP (type II). For Arg672Gly/His a fast inactivation defect was described, and for Arg669His an impairment of slow inactivation was reported. Except for the substitution for serine, we have now expressed all mutants in a human cell-line and studied them electrophysiologically. Patch-clamp recordings show an enhanced fast inactivation for all three mutations, whereas two of them reveal enhanced slow inactivation. This may reduce the number of functional sodium channels at resting membrane potential and contribute to the long-lasting periods of paralysis experienced by hypoPP patients. The gating of both histidine mutants (Arg669His, Arg672His) can be modulated by changes of extra- or intracellular pH. The inactivation defects of Arg669His and Arg672His can be alleviated by low pH to a significant degree, suggesting that the decrease of pH in muscle cells (e.g. during muscle work) might lead to an auto-compensation of functional defects. This may explain a delay or prevention of paralytic attacks in patients by slight physical activity. Moreover, the histidine residues may be the target for a potential therapeutic action by acetazolamide.
authors.affiliation: Department of Applied Physiology, University of Ulm, D-89069 Ulm, Germany.
authors.forename: Alexey
authors.initials: A
authors.lastname: Kuzmenkin
authors.forename: Vanesa
authors.initials: V
authors.lastname: Muncan
authors.forename: Karin
authors.initials: K
authors.lastname: Jurkat-Rott
authors.forename: Chao
authors.initials: C
authors.lastname: Hang
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Frank
authors.initials: F
authors.lastname: Lehmann-Horn
authors.forename: Nenad
authors.initials: N
authors.lastname: Mitrovic
mesh_terms: D001120:Arginine / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D005998:Glycine / Q000235:genetics* / Q000378:metabolism; D006639:Histidine / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006863:Hydrogen-Ion Concentration; D020514:Hypokalemic Periodic Paralysis / Q000188:drug therapy / Q000378:metabolism* / Q000503:physiopathology; D008564:Membrane Potentials / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D062553:NAV1.4 Voltage-Gated Sodium Channel; D011188:Potassium / Q000378:metabolism / Q000494:pharmacology; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism*
chemical_list: D062553:NAV1.4 Voltage-Gated Sodium Channel; C106251:SCN4A protein, human; D015222:Sodium Channels; D006639:Histidine; D001120:Arginine; D011188:Potassium; D005998:Glycine