The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors

Timothy G. Hales, Haiyan Tang, Karen A. Bollan, Sara J. Johnson, Dale P. King, Neil A. McDonald, Aixin Cheng, Christopher N. Connolly

    Research output: Contribution to journalArticle

    51 Citations (Scopus)

    Abstract

    Given the association of a ?2 mutation (R43Q) with epilepsy and the
    reduced cell surface expression of mutant receptors, we investigated a
    role for this residue in a1ß2?2 receptor assembly when present in each
    subunit. Regardless of which subunit contained the mutation, mutant GABAA
    receptors assembled poorly into functional cell surface receptors. The
    low level of functional expression gives rise to reduced GABA EC50s
    (a1(R43Q)ß2?2 and a1ß2(R43Q)?2) or reduced benzodiazepine potentiation
    of GABA-evoked currents (a1ß2?2(R43Q)). We determined that a 15-residue
    peptide surrounding R43 is capable of subunit binding, with a profile
    that reflected the orientation of subunits in the pentameric receptor.
    Subunit binding is perturbed when the R43Q mutation is present
    suggesting that this residue is critical for the formation of
    inter-subunit contacts at (+) interfaces of GABAA subunits.
    Rather than being excluded from receptors, ?2(R43Q) may form
    non-productive subunit interactions leading to a dominant negative
    effect on other receptor subtypes.

    Original languageEnglish
    Pages (from-to)120-127
    Number of pages8
    JournalMolecular and Cellular Neuroscience
    Volume29
    Issue number1
    DOIs
    Publication statusPublished - 2005

    Cite this

    Hales, Timothy G. ; Tang, Haiyan ; Bollan, Karen A. ; Johnson, Sara J. ; King, Dale P. ; McDonald, Neil A. ; Cheng, Aixin ; Connolly, Christopher N. / The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors. In: Molecular and Cellular Neuroscience. 2005 ; Vol. 29, No. 1. pp. 120-127.
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    title = "The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors",
    abstract = "Given the association of a ?2 mutation (R43Q) with epilepsy and the reduced cell surface expression of mutant receptors, we investigated a role for this residue in a1{\ss}2?2 receptor assembly when present in each subunit. Regardless of which subunit contained the mutation, mutant GABAA receptors assembled poorly into functional cell surface receptors. The low level of functional expression gives rise to reduced GABA EC50s (a1(R43Q){\ss}2?2 and a1{\ss}2(R43Q)?2) or reduced benzodiazepine potentiation of GABA-evoked currents (a1{\ss}2?2(R43Q)). We determined that a 15-residue peptide surrounding R43 is capable of subunit binding, with a profile that reflected the orientation of subunits in the pentameric receptor. Subunit binding is perturbed when the R43Q mutation is present suggesting that this residue is critical for the formation of inter-subunit contacts at (+) interfaces of GABAA subunits. Rather than being excluded from receptors, ?2(R43Q) may form non-productive subunit interactions leading to a dominant negative effect on other receptor subtypes.",
    author = "Hales, {Timothy G.} and Haiyan Tang and Bollan, {Karen A.} and Johnson, {Sara J.} and King, {Dale P.} and McDonald, {Neil A.} and Aixin Cheng and Connolly, {Christopher N.}",
    year = "2005",
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    The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors. / Hales, Timothy G.; Tang, Haiyan; Bollan, Karen A.; Johnson, Sara J.; King, Dale P.; McDonald, Neil A.; Cheng, Aixin; Connolly, Christopher N.

    In: Molecular and Cellular Neuroscience, Vol. 29, No. 1, 2005, p. 120-127.

    Research output: Contribution to journalArticle

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    T1 - The epilepsy mutation, γ2(R43Q) disrupts a highly conserved inter-subunit contact site, perturbing the biogenesis of GABAA receptors

    AU - Hales, Timothy G.

    AU - Tang, Haiyan

    AU - Bollan, Karen A.

    AU - Johnson, Sara J.

    AU - King, Dale P.

    AU - McDonald, Neil A.

    AU - Cheng, Aixin

    AU - Connolly, Christopher N.

    PY - 2005

    Y1 - 2005

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    AB - Given the association of a ?2 mutation (R43Q) with epilepsy and the reduced cell surface expression of mutant receptors, we investigated a role for this residue in a1ß2?2 receptor assembly when present in each subunit. Regardless of which subunit contained the mutation, mutant GABAA receptors assembled poorly into functional cell surface receptors. The low level of functional expression gives rise to reduced GABA EC50s (a1(R43Q)ß2?2 and a1ß2(R43Q)?2) or reduced benzodiazepine potentiation of GABA-evoked currents (a1ß2?2(R43Q)). We determined that a 15-residue peptide surrounding R43 is capable of subunit binding, with a profile that reflected the orientation of subunits in the pentameric receptor. Subunit binding is perturbed when the R43Q mutation is present suggesting that this residue is critical for the formation of inter-subunit contacts at (+) interfaces of GABAA subunits. Rather than being excluded from receptors, ?2(R43Q) may form non-productive subunit interactions leading to a dominant negative effect on other receptor subtypes.

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