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Activation of heteromeric G protein-gated inward rectifier K+ channels overexpressed by adenovirus gene transfer inhibits the excitability of hippocampal neurons

Ehrengruber, Markus U. and Doupnik, Craig A. and Xu, Youfeng and Garvey, Justine and Jasek, Mark C. and Lester, Henry A. and Davidson, Norman (1997) Activation of heteromeric G protein-gated inward rectifier K+ channels overexpressed by adenovirus gene transfer inhibits the excitability of hippocampal neurons. Proceedings of the National Academy of Sciences of the United States of America, 94 (13). pp. 7070-7075. ISSN 0027-8424. PMCID PMC21286.

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G protein-gated inward rectifier K+ channel subunits 1-4(GIRK1-4) have been cloned from neuronal and atrial tissue and function as heterotetramers. To examine the inhibition of neuronal excitation by GIRKs, we overexpressed GIRKs in cultured hippocampal neurons from 18 day rat embryos, which normally lack or show low amounts of GIRK protein and currents. Adenoviral recombinants containing the cDNAs for GIRK1, GIRK2, GIRK4, and the serotonin 1A receptor were constructed. Typical GIRK currents could be activated by endogenous GABA(B), serotonin 5-HT1A, and adenosine A1 receptors in neurons coinfected with GIRK1+2 or GIRK1+4. Under current clamp, GIRK activation increased the cell membrane conductance by 1- to 2-fold, hyperpolarized the cell by 11-14 mV,and inhibited action potential firing by increasing, the threshold current for firing by 2- to 3-fold. These effects were not found in non- and mock-infected neurons, and were similar to the effects of muscarinic stim ulation of native GIRK currents in atrial myocytes. Two inhibitory effects of GIRK activation, hyperpolarization and diminution of depolarizing pulses, were simulated from the experimental data. These inhibitory effects are physiologically important in the voltage range between the resting membrane potential and the potential where voltage-gated Na+ and K+ currents are activated; that is where GIRK currents are outward.

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Lester, Henry A.0000-0002-5470-5255
Additional Information:© 1997 National Academy of Sciences. Contributed by Norman Davidson, April 16, 1997. We thank S. L. McKinney for the primary cell cultures, B. W. Henkle for oocyte preparation, C. Chavkin for help with GIRK antibodies, P. Kofuji for construction of the Shaker plasmid and helpful comments, C. Lin for construction of Ad5HT1AR, S. J. Stary for advice on the adenovirus technique, and L. Byerly for instruction in electrophysiology. This work was supported by the National Institute of Mental Health, National Institute of General Medical Sciences, Human Frontier Science Program, the Swiss National Science Foundation (Fellowships 81BE-40054 and 823A-042966 to M.U.E.), and the American Heart Association (fellowship to C.A.D.). 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
National Institute of Mental Health (NIMH)UNSPECIFIED
National Institute of General Medical SciencesUNSPECIFIED
Human Frontier Science ProgramUNSPECIFIED
Swiss National Science Foundation (SNSF)81BE-40054
Swiss National Science Foundation (SNSF)823A-042966
American Heart AssociationUNSPECIFIED
Subject Keywords:functional expression, mediated transfer, rat hippocampus, pyramidal cells, receptors, serotonin, cloning, family, electrophysiology, rectification
Issue or Number:13
PubMed Central ID:PMC21286
Record Number:CaltechAUTHORS:EHRpnas97
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Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:918
Deposited By: Tony Diaz
Deposited On:08 Nov 2005
Last Modified:02 Oct 2019 22:38

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