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

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    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
    Issue number1
    Publication statusPublished - 2005

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