title: GABA(A) receptor composition is determined by distinct assembly signals within alpha and beta subunits.
abstract: Key to understanding how receptor diversity is achieved and controlled is the identification of selective assembly signals capable of distinguishing between other subunit partners. We have identified that the beta1-3 subunits exhibit distinct assembly capabilities with the gamma2L subunit. Similarly, analysis of an assembly box in alpha1-(57-68) has revealed an absolute requirement for this region in the assembly of alphabeta receptors. Furthermore, a selective requirement for a single amino acid (Arg-66), previously shown to be essential for the formation of the low affinity GABA binding site, is observed. This residue is critical for the assembly of alpha1beta2 but not alpha1beta1 or alpha1beta3 receptors. We have confirmed the ability of the previously identified GKER signal in beta3 to direct the assembly of betagamma receptors. The GKER signal is also involved in driving assembly with the alpha1 subunit, conferring the ability to assemble with alpha1(R66A) on the beta2 subunit. Although this signal is sufficient to permit the formation of beta2gamma2 receptors, it is not necessary for beta3gamma2 receptor formation, suggesting the existence of alternative assembly signals. These findings support the belief that GABA(A) receptor assembly occurs via defined pathways to limit the receptor diversity.
authors.affiliation: Department of Pharmacology and Neuroscience, Ninewells Medical School, University of Dundee, Dundee DD1 9SY, Scotland.
authors.forename: Karen
authors.initials: K
authors.lastname: Bollan
authors.forename: Dale
authors.initials: D
authors.lastname: King
authors.forename: Laura A
authors.initials: LA
authors.lastname: Robertson
authors.forename: Kenneth
authors.initials: K
authors.lastname: Brown
authors.forename: Pamela M
authors.initials: PM
authors.lastname: Taylor
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Connolly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D051379:Mice; D008969:Molecular Sequence Data; D021122:Protein Subunits / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D018079:Receptors, GABA / Q000032:analysis / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013329:Structure-Activity Relationship
chemical_list: D021122:Protein Subunits; D018079:Receptors, GABA; D011994:Recombinant Proteins