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The Journal of Neuroscience, December 1, 2001, 21(23):9124-9133

Alternate Use of Distinct Intersubunit Contacts Controls GABA_A Receptor Assembly and Stoichiometry

Thomas Klausberger^{1, 3}, Isabella Sarto^{1, 3}, Noosha Ehya^{1, 3}, Karoline Fuchs³, Roman Furtmüller^{3, 4}, Bernd Mayer², Sigismund Huck⁴, and Werner Sieghart^{1, 3}

¹ Section of Biochemical Psychiatry, University Clinic for Psychiatry, ² Institute for Theoretical Chemistry and Molecular Structural Biology, and Divisions of ³ Biochemistry and Molecular Biology and ⁴ Cellular Physiology, Brain Research Institute, University of Vienna, A-1090 Vienna, Austria

GABA_A receptors are the major inhibitory transmitter receptors in the CNS. Recombinant GABA_A receptors composed of ₁₃₂ subunits have been demonstrated to assemble as pentamers consisting of two ₁, two ₃, and one ₂ subunit. Using truncated and chimeric ₁ subunits, we identified the ₁(80-100) sequence as a major binding site for ₂ subunits. In addition, we demonstrated its direct interaction with ₂(91-104), a sequence that previously has been identified to form the contact to ₁ subunits. The observation that the amino acid residues ₁P96 and ₁H101, which can be photolabeled by [³H]flunitrazepam, are located within or adjacent to the ₁(80-100) sequence, indicates that the benzodiazepine binding site of GABA_A receptors is located close to this intersubunit contact. The observation that ₁(80-100) interacts with ₂ but not with ₃ subunits indicates the existence of an additional ₃ binding site on ₁ subunits. The preferred alternate use of the ₂ and ₃ binding sites in two different ₁ subunits of the same receptor ensures the incorporation of only a single ₂ subunit and thus, determines subunit stoichiometry of ₁₃₂ receptors. Distinct binding sites and their alternate use can therefore explain how subunits of hetero-oligomeric transmembrane proteins assemble into a defined protein complex.

Key words: GABA_A receptor; assembly; subunit interface; structure; subunit stoichiometry; benzodiazepine binding pocket

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21239124-10$05.00/0

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