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J Biol Chem, Vol. 273, Issue 31, 19708-19714, July 31, 1998

The Human Glycine Receptor Subunit 3
GLRA3 GENE STRUCTURE, CHROMOSOMAL LOCALIZATION, AND FUNCTIONAL CHARACTERIZATION OF ALTERNATIVE TRANSCRIPTS

Zeljko Nikolic, Bodo Laube^§, Ruthild G. Weber^¶, Peter Lichter^¶, Petra Kioschis, Annemarie Poustka, Cornel Mülhardt, and Cord-Michael Becker

From the  Institut für Biochemie, Universität Erlangen-Nürnberg, Fahrstrasse 17, D-91054 Erlangen, Germany, the ^§ Max-Planck-Institut für Hirnforschung, Deutschordenstrasse 46, D-60528 Frankfurt, Germany, the ^¶ Abteilung Organisation Komplexer Genome and the  Abteilung Molekulare Genomanalyse, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany

The neuronal glycine receptor is a ligand-gated chloride channel composed of ligand binding  and structural  polypeptides. Homology screening of a human fetal brain cDNA library resulted in the identification of two alternative splice variants of the glycine receptor 3 subunit. The amino acid sequence predicted for the 3L variant was largely identical to the corresponding rat subunit. In contrast, the novel splice variant 3K lacked the coding sequence for 15 amino acids located within the cytoplasmic loop connecting transmembrane spanning region 3 (TM3) and TM4. Using P1 artificial chromosome (PAC) clones, the structure of the GLRA3 gene was elucidated and its locus assigned to human chromosomal bands 4q33-q34 by fluorescence in situ hybridization. Two transcripts of 2.4 and 9 kilobases, corresponding to 3L and 3K, respectively, were identified and found to be widely distributed throughout the human central nervous system. Structural analysis of the GLRA3 gene revealed that the 3K transcript resulted from a complex splice event where excision of the novel exon 8A comprising the alternative sequence of 45 base pairs coincides with the persistence of a large intronic sequence in the 3'-untranslated region. Functional expression in HEK 293 cells of 3L and 3K subunits resulted in the formation of glycine-gated chloride channels that differed significantly in desensitization behavior, thus defining the cytoplasmic loop as an important determinant of channel inactivation kinetics.

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