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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. and Kofuji, Paulo and Dougherty, Dennis A. and Davidson, Norman and Lester, Henry A. (1996) A regenerative link in the ionic fluxes through the weaver potassium channel underlies the pathophysiology of the mutation. Proceedings of the National Academy of Sciences of the United States of America, 93 (26). pp. 15429-15434. ISSN 0027-8424. PMCID PMC26421. doi:10.1073/pnas.93.26.15429.

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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(beta gamma) 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 (wv-GIRK2) 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 the 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.

Item Type:Article
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URLURL TypeDescription CentralArticle
Dougherty, Dennis A.0000-0003-1464-2461
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1996 by the National Academy of Sciences. Contributed by Norman Davidson, October 16, 1996. We thank N. Dascal for comments. This work was supported by grants from the National Institute of Mental Health (MH-49176), the National Institute of General Medical Sciences (GM-29836), and the National Institute of Neurological Disorders and Stroke (NS-34407). P.K. held fellowships from the Guenther Foundation and the American Heart Association. The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Funding AgencyGrant Number
Guenther FoundationUNSPECIFIED
American Heart AssociationUNSPECIFIED
Issue or Number:26
PubMed Central ID:PMC26421
Record Number:CaltechAUTHORS:SILpnas96
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Official Citation: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 Proceedings of the National Academy of Sciences Dec 1996, 93 (26) 15429-15434; DOI: 10.1073/pnas.93.26.15429
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:914
Deposited By: Tony Diaz
Deposited On:08 Nov 2005
Last Modified:08 Nov 2021 19:06

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