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Subcellular localization and endocytosis of homomeric gamma 2 subunit splice variants of gamma-aminobutyric acid type A receptors

Connolly, CN; Uren, JM; Thomas, P; Gorrie, GH; Gibson, A; Smart, TG; Moss, SJ; (1999) Subcellular localization and endocytosis of homomeric gamma 2 subunit splice variants of gamma-aminobutyric acid type A receptors. MOL CELL NEUROSCI , 13 (4) 259 - 271.

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Abstract

The expression of alpha and beta gamma-aminobutyric acid type A receptor subunits produces GABA-gated channels which require the incorporation of either the gamma 2 or gamma 3 subunit for benzodiazepine modulation. Here we examine the role of the gamma 2 subunit splice variants, gamma 2S and gamma 2L which differ by eight amino acids in the major intracellular domain, in mediating cell surface expression. Using immunocytochemistry we have demonstrated that when expressed alone, the gamma 2S subunit can access the cell surface and internalize constitutively. In contrast, alpha 1, beta 2 and gamma 2L are retained predominantly in the endoplasmic reticulum (ER) when expressed alone. Replacing the insert which differentiates gamma 2L from gamma 2S (LLRMFSFK) with eight alanines produces a phenotype identical to gamma 2S. Both gamma 2 subunits fail to produce high molecular weight oligomers observed for alpha 1 beta 2 and alpha 1 beta 2 gamma 2 heterooligomers and do not form functional ion channels. Surface expression of gamma 2S is repressed upon the coexpression of alpha 1 or beta 2 subunits, resulting in ER-retained heterooligomers, suggesting that homomeric gamma 2S is unlikely to occur in vivo. However, its independent maturation to surface competence and preferential assembly with alpha and beta subunits may ensure the production of functional benzodiazepine-sensitive receptors. Furthermore, the presence of the gamma 2 subunit appears to confer an endocytotic capacity to these heterooligomeric receptors.

Type: Article
Title: Subcellular localization and endocytosis of homomeric gamma 2 subunit splice variants of gamma-aminobutyric acid type A receptors
Keywords: GABA(A) receptor, recombinant, assembly, endocytosis, RECOMBINANT GABA(A) RECEPTOR, DEPENDENT PROTEIN-KINASE, A RECEPTORS, BENZODIAZEPINE RECEPTORS, TRANSFERRIN RECEPTORS, INTRACELLULAR DOMAINS, CHANNEL PROPERTIES, BETA-SUBUNITS, ION CHANNELS, CELL-SURFACE
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology
URI: http://discovery.ucl.ac.uk/id/eprint/120427
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