A regenerative link in the ionic fluxes through the weaver potassium channel underlies the pathophysiology of the mutation

Scott K Silverman, Paulo Kofuji, Dennis A. Dougherty, Norman Davidson, Henry A. Lester

Research output: Contribution to journalArticle

Abstract

The homozygous weaver mouse displays neuronal degeneration in several brain regions. Previous experiments in heterologous expression systems showed that the G protein-gated inward rectifier K+ channel (GIRK2) bearing the weaver pore-region GYG-to-SYG mutation (i) is not activated by G(βγ) subunits, but instead shows constitutive activation, and (ii) is no longer a K+-selective channel but conducts Na+ as well. The present experiments on weaverGIRK2 (wvGIRK2) expressed in Xenopus oocytes show that the level of constitutive activation depends on intracellular Na+ concentration. In particular, manipulations that decrease intracellular Na+ produce a component of Na+-permeable current activated via a G protein pathway. Therefore, constitutive activation may not arise because the weaver mutation directly alters that gating transitions of the channel protein. Instead, there may be a regenerative cycle of Na+ influx through the wvGIRK2 channel, leading to additional Na+ activation. We also show that the wvGIRK2 channel is permeable to Ca2+, providing an additional mechanism for the degeneration that characterizes the weaver phenotype. We further demonstrate that the GIRK4 channel bearing the analogous weaver mutation has properties similar to those of the wvGIRK2 channel, providing a glimpse of the selective pressures that have maintained the GYG sequence in nearly all known K+ channels.

Original languageEnglish (US)
Pages (from-to)15429-15434
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume93
Issue number26
DOIs
StatePublished - Dec 24 1996

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Potassium Channels
GTP-Binding Proteins
Mutation
Neurologic Mutant Mice
Inwardly Rectifying Potassium Channel
Xenopus
Oocytes
Phenotype
Brain
Proteins

ASJC Scopus subject areas

  • General

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A regenerative link in the ionic fluxes through the weaver potassium channel underlies the pathophysiology of the mutation. / Silverman, Scott K; Kofuji, Paulo; Dougherty, Dennis A.; Davidson, Norman; Lester, Henry A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 93, No. 26, 24.12.1996, p. 15429-15434.

Research output: Contribution to journalArticle

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