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Molecular Pharmacology

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Research ArticleArticle

γ-Aminobutyric Acid Type A α4, β2, and δ Subunits Assemble to Produce More Than One Functionally Distinct Receptor Type

Megan M. Eaton, John Bracamontes, Hong-Jin Shu, Ping Li, Steven Mennerick, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology December 2014, 86 (6) 647-656; DOI: https://doi.org/10.1124/mol.114.094813
Megan M. Eaton
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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John Bracamontes
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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Hong-Jin Shu
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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Ping Li
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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Steven Mennerick
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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Joe Henry Steinbach
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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Gustav Akk
Department of Anesthesiology (M.M.E., J.B., P.L., J.H.S., G.A.), Department of Psychiatry (H.-J.S., S.M.), and Taylor Family Institute for Innovative Psychiatric Research (S.M., J.H.S., G.A.), Washington University School of Medicine, St. Louis, Missouri
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Abstract

Native γ-aminobutyric acid (GABA)A receptors consisting of α4, β1–3, and δ subunits mediate responses to the low, tonic concentration of GABA present in the extracellular milieu. Previous studies on heterologously expressed α4βδ receptors have shown a large degree of variability in functional properties, including sensitivity to the transmitter. We studied properties of α4β2δ receptors employing free subunits and concatemeric constructs, expressed in Xenopus oocytes, HEK 293 cells, and cultured hippocampal neurons. The expression system had a strong effect on the properties of receptors containing free subunits. The midpoint of GABA activation curve was 10 nM for receptors in oocytes versus 2300 nM in HEK cells. Receptors activated by the steroid alfaxalone had an estimated maximal open probability of 0.6 in oocytes and 0.01 in HEK cells. Irrespective of the expression system, receptors resulting from combining the tandem construct β2-δ and a free α4 subunit exhibited large steroid responses. We propose that free α4, β2, and δ subunits assemble in different configurations with distinct properties in oocytes and HEK cells, and that subunit linkage can overcome the expression system-dependent preferential assembly of free subunits. Hippocampal neurons transfected with α4 and the picrotoxin-resistant δ(T269Y) subunit showed large responses to alfaxalone in the presence of picrotoxin, suggesting that α4βδ receptors may assemble in a similar configuration in neurons and oocytes.

Footnotes

    • Received July 16, 2014.
    • Accepted September 19, 2014.
  • This work was supported by the National Institutes of Health National Institute of General Medical Sciences [Grants P01-GM047969 and R01-GM108580] and National Institute of Mental Health [Grants R21-MH099658 and R01-MH078823]. J.H.S. is the Russell and Mary Shelden Professor of Anesthesiology.

  • dx.doi.org/10.1124/mol.114.094813.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 86 (6)
Molecular Pharmacology
Vol. 86, Issue 6
1 Dec 2014
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Research ArticleArticle

Distinct Types of the α4β2δ GABAA Receptor

Megan M. Eaton, John Bracamontes, Hong-Jin Shu, Ping Li, Steven Mennerick, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology December 1, 2014, 86 (6) 647-656; DOI: https://doi.org/10.1124/mol.114.094813

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Research ArticleArticle

Distinct Types of the α4β2δ GABAA Receptor

Megan M. Eaton, John Bracamontes, Hong-Jin Shu, Ping Li, Steven Mennerick, Joe Henry Steinbach and Gustav Akk
Molecular Pharmacology December 1, 2014, 86 (6) 647-656; DOI: https://doi.org/10.1124/mol.114.094813
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