Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis.

Fenfen Wu, Wentao Mi, Stephen C. Cannon

Research output: Contribution to journalArticle

16 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3766-3774
Number of pages9
JournalBrain : a journal of neurology
Volume136
Issue numberPt 12
StatePublished - Dec 2013

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Hypokalemic Periodic Paralysis
Bumetanide
Mutation
Sodium Channels
Calcium Channels
Membrane Potentials
Chlorides
Muscle Weakness
Genes
Potassium
Stroke
Insulin
Glucose
Muscles
Therapeutics

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. / Wu, Fenfen; Mi, Wentao; Cannon, Stephen C.

In: Brain : a journal of neurology, Vol. 136, No. Pt 12, 12.2013, p. 3766-3774.

Research output: Contribution to journalArticle

Wu, Fenfen ; Mi, Wentao ; Cannon, Stephen C. / Beneficial effects of bumetanide in a CaV1.1-R528H mouse model of hypokalaemic periodic paralysis. In: Brain : a journal of neurology. 2013 ; Vol. 136, No. Pt 12. pp. 3766-3774.
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