title: Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis.
abstract: Transient attacks of weakness in hypokalaemic periodic paralysis are caused by reduced fibre excitability from paradoxical depolarization of the resting potential in low potassium. Mutations of calcium channel and sodium channel genes have been identified as the underlying molecular defects that cause instability of the resting potential. Despite these scientific advances, therapeutic options remain limited. In a mouse model of hypokalaemic periodic paralysis from a sodium channel mutation (NaV1.4-R669H), we recently showed that inhibition of chloride influx with bumetanide reduced the susceptibility to attacks of weakness, in vitro. The R528H mutation in the calcium channel gene (CACNA1S encoding CaV1.1) is the most common cause of hypokalaemic periodic paralysis. We developed a CaV1.1-R528H knock-in mouse model of hypokalaemic periodic paralysis and show herein that bumetanide protects against both muscle weakness from low K+ challenge in vitro and loss of muscle excitability in vivo from a glucose plus insulin infusion. This work demonstrates the critical role of the chloride gradient in modulating the susceptibility to ictal weakness and establishes bumetanide as a potential therapy for hypokalaemic periodic paralysis arising from either NaV1.4 or CaV1.1 mutations.
authors.affiliation: 1 Department of Neurology and Neurotherapeutics, UT Southwestern Medical Centre, Dallas, Texas, USA.
authors.forename: Fenfen
authors.initials: F
authors.lastname: Wu
authors.forename: Wentao
authors.initials: W
authors.lastname: Mi
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Cannon
mesh_terms: D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D001120:Arginine / Q000235:genetics; D002034:Bumetanide / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000235:genetics*; D002257:Carbonic Anhydrase Inhibitors / Q000494:pharmacology; D004195:Disease Models, Animal; D019054:Evoked Potentials, Motor / Q000187:drug effects / Q000235:genetics; D005665:Furosemide / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism; D006639:Histidine / Q000235:genetics; D020514:Hypokalemic Periodic Paralysis / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D066298:In Vitro Techniques; D007537:Isometric Contraction / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000503:physiopathology; D009154:Mutation / Q000235:genetics*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000627:therapeutic use*
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; D002257:Carbonic Anhydrase Inhibitors; D049994:Sodium Potassium Chloride Symporter Inhibitors; D002034:Bumetanide; D006639:Histidine; D005665:Furosemide; D001120:Arginine; D005947:Glucose; D000086:Acetazolamide
keywords: NKCC transporter; acetazolamide; calcium channel; skeletal muscle