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Volume 17, Number 4, Issue of February 15, 1997 pp. 1350-1362
Copyright ©1997 Society for Neuroscience

Ligand-Gated Ion Channel Subunit Partnerships: GABA_A Receptor ₆ Subunit Gene Inactivation Inhibits  Subunit Expression

Received Oct. 10, 1996; revised Nov. 25, 1996; accepted Nov. 26, 1996.

A. Jones^1, , E. R. Korpi^2, , R. M. McKernan^3, , R. Pelz^4, , Z. Nusser⁵, R. Mäkelä², J. R. Mellor¹, S. Pollard⁶, S. Bahn¹, F. A. Stephenson⁶, A. D. Randall¹, W. Sieghart⁴, P. Somogyi⁵, A. J. H. Smith¹, and W. Wisden¹

¹ Medical Research Council Laboratory of Molecular Biology, Medical Research Council Centre, Cambridge CB2 2QH, United Kingdom, ² Department of Pharmacology and Clinical Pharmacology, University of Turku, Fin-20014 Turku, Finland, Department of Alcohol Research, National Public Health Institute, Fin-00180 Helsinki, Finland, ³ Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, CM20 2QR, United Kingdom, ⁴ University Clinic for Psychiatry, Department of Biochemical Psychiatry, 1090 Vienna, Austria, ⁵ Medical Research Council Anatomical Neuropharmacology Unit, Oxford University Department of Pharmacology, Oxford, OX1 3TH, United Kingdom, and ⁶ School of Pharmacy, University of London, Brunswick Square, London, WC1N 1AX, United Kingdom

Cerebellar granule cells express six GABA_A receptor subunits abundantly (₁, ₆, ₂, ₃, ₂, and ) and assemble various pentameric receptor subtypes with unknown subunit compositions; however, the rules guiding receptor subunit assembly are unclear. Here, removal of intact ₆ protein from cerebellar granule cells allowed perturbations in other subunit levels to be studied. Exon 8 of the mouse ₆ subunit gene was disrupted by homologous recombination. In ₆ / granule cells, the  subunit was selectively degraded as seen by immunoprecipitation, immunocytochemistry, and immunoblot analysis with  subunit-specific antibodies. The  subunit mRNA was present at wild-type levels in the mutant granule cells, indicating a post-translational loss of the  subunit. These results provide genetic evidence for a specific association between the ₆ and  subunits. Because in ₆ / neurons the remaining ₁, _2/3, and ₂ subunits cannot rescue the  subunit, certain potential subunit combinations may not be found in wild-type cells.

Key words: GABA_A receptor; ₆ subunit; granule cell; cerebellum; homologous recombination; gene targeting; transgenic mice; knockout mice; ligand-gated ion channel; subunit sorting; subunit assembly; internal ribosome entry site; dicistronic mRNA; muscimol; SR95531; Ro 15-4513; flunitrazepam

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