A Novel Glycine Receptor β Subunit Splice Variant Predicts an Unorthodox Transmembrane Topology

The inhibitory glycine receptor is a ligand-gated ion channel with a pentameric assembly from ligand binding α and structural β subunits. In addition to α subunit gene variants (α1–α4) and developmental alterations in subunit composition of the receptor protein complex, alternative splicing of α subunits has been found to contribute to glycine receptor heterogeneity. Here, we describe a novel splice variant of the glycine receptor β subunit from mouse central nervous system, prevailing in macroglial cells, predominantly in astrocytes and extraneural tissues. As predicted by its cDNA sequence, the novel subunit βΔ7 lacks amino acid positions 251–302 encoded by exon 7 of the Glrb gene. Transcripts and antigen of βΔ7 were detected in cerebral cortex, liver, and heart. Lack of exon 7 results in a profoundly altered prediction of transmembrane topology as βΔ7 lacks TM1 and TM2 present in the full-length variant. Despite these topological alterations, in vitro studies showed that the βΔ7 polypeptide integrates into the plasma membrane, forming receptor complexes with the α1 subunit and gephyrin. Our data demonstrate that a topology deviating from the classical four transmembrane-fold is compatible with formation of glycine receptor protein complexes. However, co-expression of α1 with βΔ7 subunits did not change glycine receptor channel properties. Rather, the high level of expression in non-neuronal cells having intimate contact with synaptic regions may account for a yet unknown function of this splice variant βΔ7 in glycinergic neurotransmission. The inhibitory glycine receptor is a ligand-gated ion channel with a pentameric assembly from ligand binding α and structural β subunits. In addition to α subunit gene variants (α1–α4) and developmental alterations in subunit composition of the receptor protein complex, alternative splicing of α subunits has been found to contribute to glycine receptor heterogeneity. Here, we describe a novel splice variant of the glycine receptor β subunit from mouse central nervous system, prevailing in macroglial cells, predominantly in astrocytes and extraneural tissues. As predicted by its cDNA sequence, the novel subunit βΔ7 lacks amino acid positions 251–302 encoded by exon 7 of the Glrb gene. Transcripts and antigen of βΔ7 were detected in cerebral cortex, liver, and heart. Lack of exon 7 results in a profoundly altered prediction of transmembrane topology as βΔ7 lacks TM1 and TM2 present in the full-length variant. Despite these topological alterations, in vitro studies showed that the βΔ7 polypeptide integrates into the plasma membrane, forming receptor complexes with the α1 subunit and gephyrin. Our data demonstrate that a topology deviating from the classical four transmembrane-fold is compatible with formation of glycine receptor protein complexes. However, co-expression of α1 with βΔ7 subunits did not change glycine receptor channel properties. Rather, the high level of expression in non-neuronal cells having intimate contact with synaptic regions may account for a yet unknown function of this splice variant βΔ7 in glycinergic neurotransmission. Glycine receptors (GlyRs) 2The abbreviations used are: GlyR, glycine receptor; Endo H, endoglycosidase H; RT, reverse transcription; NHS-S-S, sulfo-N-hydroxysulfosuccinimide; TM, transmembrane domain; GABA, γ-aminobutyric acid. belong to the superfamily of Cys-loop receptors, which also include nicotinic acetylcholine receptors, ionotropic γ-aminobutyric acid receptors (GABAA and GABAC), and the ionotropic serotonin receptor subtype 5HT3 (1Lester H.A. Dibas M.I. Dahan D.S. Leite J.F. Dougherty D.A. Trends Neurosci. 2004; 27: 329-336Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar). GlyRs are pentameric assemblies of five subunits surrounding a central ion-conducting pore that mediates rapid inhibitory neurotransmission in the spinal cord and brainstem (2Corringer P.J. Le Novere N. Changeux J.P. Annu. Rev. Pharmacol. Toxicol. 2000; 40: 431-458Crossref PubMed Scopus (706) Google Scholar, 3Langosch D. Thomas L. Betz H. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 7394-7398Crossref PubMed Scopus (309) Google Scholar). Common features of all Cys-loop receptor subunits include four transmembrane regions (TM1–TM4), where TM2 forms the ion channel pore, and a large extracellular N-terminal ligand-binding domain. This domain shows significant structural homology to the acetylcholine-binding protein of Lymnaea stagnalis (4Brejc K. van Dijk W.J. Klaassen R.V. Schuurmans M. van Der Oost J. Smit A.B. Sixma T.K. Nature. 2001; 411: 269-276Crossref PubMed Scopus (1580) Google Scholar), a member of the immunoglobulin-like superfamily of proteins. By association of β subunits with the intracellular anchor protein gephyrin, GlyRs are clustered at the postsynaptic membrane. The gephyrin binding motif of the β subunit polypeptide has been mapped to the long intracellular TM3–4 loop (5Kim E.Y. Schrader N. Smolinsky B. Bedet C. Vannier C. Schwarz G. Schindelin H. EMBO J. 2006; (in press)Google Scholar, 6Kneussel M. Hermann A. Kirsch J. Betz H. J. Neurochem. 1999; 72: 1323-1326Crossref PubMed Scopus (73) Google Scholar, 7Meier J. Vannier C. Serge A. Triller A. Choquet D. Nat. Neurosci. 2001; 4: 253-260Crossref PubMed Scopus (225) Google Scholar, 8Meyer G. Kirsch J. Betz H. Langosch D. Neuron. 1995; 15: 563-572Abstract Full Text PDF PubMed Scopus (350) Google Scholar, 9Sola M. Bavro V.N. Timmins J. Franz T. Ricard-Blum S. Schoehn G. Ruigrok R.W. Paarmann I. Saiyed T. O'Sullivan G.A. Schmitt B. Betz H. Weissenhorn W. EMBO J. 2004; 23: 2510-2519Crossref PubMed Scopus (124) Google Scholar). The GlyR β subunit gene is widely transcribed throughout the central nervous system of neonatal and adult rodents. Starting at embryonic day 14, β transcripts are first detectable by in situ hybridization in rat spinal cord and telencephalon (10Grenningloh G. Pribilla I. Prior P. Multhaup G. Beyreuther K. Taleb O. Betz H. Neuron. 1990; 4: 963-970Abstract Full Text PDF PubMed Scopus (203) Google Scholar, 11Malosio M.L. Marqueze-Pouey B. Kuhse J. Betz H. EMBO J. 1991; 10: 2401-2409Crossref PubMed Scopus (456) Google Scholar). Expression of the ligand binding α subunit variants (α1–α4) is highly regulated during development (12Akagi H. Hirai K. Hishinuma F. Neurosci. Res. 1991; 11: 28-40Crossref PubMed Scopus (27) Google Scholar, 13Becker C.M. Hoch W. Betz H. EMBO J. 1988; 7: 3717-3726Crossref PubMed Scopus (297) Google Scholar). Further GlyR subunit heterogeneity is generated by alternative splicing and RNA editing (α1 and α1ins; α2–3A and -3B; α3L and α3K) (11Malosio M.L. Marqueze-Pouey B. Kuhse J. Betz H. EMBO J. 1991; 10: 2401-2409Crossref PubMed Scopus (456) Google Scholar, 14Meier J.C. Henneberger C. Melnick I. Racca C. Harvey R.J. Heinemann U. Schmieden V. Grantyn R. Nat. Neurosci. 2005; 8: 736-744Crossref PubMed Scopus (93) Google Scholar, 15Nikolic Z. Laube B. Weber R.G. Lichter P. Kioschis P. Poustka A. Mulhardt C. Becker C.M. J. Biol. Chem. 1998; 273: 19708-19714Abstract Full Text Full Text PDF PubMed Scopus (91) Google Scholar). Whereas, there are no reports about alternative splicing of the β subunit, aberrant splicing of GlyR β subunit transcripts underlies neurological disorders in a mouse mutant and human hyperekplexia (16Rees M.I. Lewis T.M. Kwok J.B. Mortier G.R. Govaert P. Snell R.G. Schofield P.R. Owen M.J. Hum. Mol. Genet. 2002; 11: 853-860Crossref PubMed Google Scholar). The pathological phenotype of the recessive mouse mutant spastic, where a LINE1 element is inserted into intron 5 of the Glrb gene results in exon skipping and a dramatic reduction in GlyR number (17Kingsmore S.F. Giros B. Suh D. Bieniarz M. Caron M.G. Seldin M.F. Nat. Genet. 1994; 7: 136-141Crossref PubMed Scopus (190) Google Scholar, 18Mulhardt C. Fischer M. Gass P. Simon-Chazottes D. Guenet J.L. Kuhse J. Betz H. Becker C.M. Neuron. 1994; 13: 1003-1015Abstract Full Text PDF PubMed Scopus (170) Google Scholar). Likewise, compound heterozygote mutations of the human β subunit gene GLRB, with one allele resulting in skipping of exon 5, cause the human neurological disorder hyperekplexia (16Rees M.I. Lewis T.M. Kwok J.B. Mortier G.R. Govaert P. Snell R.G. Schofield P.R. Owen M.J. Hum. Mol. Genet. 2002; 11: 853-860Crossref PubMed Google Scholar). As from D. Thomas L. Betz H. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 7394-7398Crossref PubMed Scopus (309) Google and ion channel J. R. S. A. G. Betz H. Laube B. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google pentameric GlyRs a subunit of GlyR α subunits are to into in cells (10Grenningloh G. Pribilla I. Prior P. Multhaup G. Beyreuther K. Taleb O. Betz H. Neuron. 1990; 4: 963-970Abstract Full Text PDF PubMed Scopus (203) Google Scholar, H. Hirai K. Hishinuma F. Neurosci. Res. 1991; 11: 28-40Crossref PubMed Scopus (27) Google Scholar, J. Schmieden V. Betz H. J. Biol. Chem. 1990; Full Text PDF PubMed Google Scholar, J. Schmieden V. Betz H. Neuron. 1990; Full Text PDF PubMed Scopus Google Scholar). with α β subunits into GlyRs and contribute to intracellular during protein and receptor the β subunit and of GlyR as by altered channel and of of as with α1 receptors R. J. Biol. Chem. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar, I. T. Langosch D. J. Betz H. EMBO J. 11: PubMed Scopus Google Scholar, J.L. J. Neurochem. 2001; PubMed Scopus Google Scholar). As a of the of the β subunit with gephyrin, GlyRs are clustered at the postsynaptic membrane. is highly at the of the inhibitory postsynaptic and with GlyRs and receptor variants in spinal and regions J. Grantyn R. J. Neurosci. 2004; PubMed Scopus Google Scholar, M. Kirsch J. U. U. H. Betz H. H. J. 1995; PubMed Scopus Google Scholar, J. Neurosci. 8: PubMed Scopus Google Scholar, B. P. Res. 2005; PubMed Scopus Google Scholar, H. P. Becker C.M. Res. 1998; PubMed Scopus Google Scholar). In this we by a novel GlyR β subunit splice variant that lacks exon This is highly in cells of rat spinal cord and in astrocytes from mouse The variant βΔ7 also detectable in RNA from mouse spinal cortex, liver, and heart. of exon 7 altered transmembrane topology of the β polypeptide with TM1 and TM2 expression that βΔ7 forms receptor complexes with the ligand binding α1 subunit as as the anchor protein gephyrin. RNA and cDNA and of reverse and were as F. Mulhardt C. A. Becker C.M. H. J. Neurochem. PubMed Scopus Google Scholar, B. P. F. J. Neuron. Full Text PDF PubMed Scopus Google Scholar). In were and RNA by to the with to by from of the its into a of of of and of by of of reverse to a of for at by at The in a of of reverse of and 5 of and of used to 5 at for for and at for the were to and for of cDNA were β and in the first and of in the were and (10Grenningloh G. Pribilla I. Prior P. Multhaup G. Beyreuther K. Taleb O. Betz H. Neuron. 1990; 4: 963-970Abstract Full Text PDF PubMed Scopus (203) Google Scholar). to of from β cDNA by the of the As a cDNA from spinal cord RNA used of RNA from used of RNA RNA from no were and into RNA were from spinal cord and spinal and from the RNA with and the RNA with and cDNA as in the The were for the β subunit and for used for of β βΔ7 are: for were by and of and cells were of cells were a C. H. Mol. Biol. 7: PubMed Scopus Google Scholar). protein as a for for protein and were 5 and the cells were in the of for of and of spinal cord and were as F. Mulhardt C. A. Becker C.M. H. J. Neurochem. PubMed Scopus Google Scholar). cells were that were the of the and a were the in a A. B. PubMed Scopus Google Scholar). of a of and from to in were and cells were as F. Mulhardt C. A. Becker C.M. H. J. Neurochem. PubMed Scopus Google Scholar, K. F. G. K. M. H. C. J. Neurosci. 23: PubMed Google Scholar). were with at and at 5 used in the with the of 5 The with a of and The from cells were by of ligand of ligand with a that the in a of a for of The of to with the to with were at a of were at were from The of these of and in of cells in as with Z. J. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In of protein with and were with of for at were by the in for 5 Endo were in at for Endo the the of and the βΔ7 The to a The and of the were by high and of The to the were with of at 14, and The first the first βΔ7 generated by of with a from cells with the β and cells were in 5 and a were from by for were in in and a of protein were from cells and mouse as H. Becker C.M. Schofield P.R. G. H. Betz H. Neuron. Full Text PDF PubMed Scopus Google Scholar). of β βΔ7 the and were The β subunits were detected with the of the α subunits for of gephyrin a were by the system with cells were in in for in and with in for at and with for at the for were a were in and in and for at by with in for at protein complexes were by the at Prior to a for complexes were with protein a at and the at The were by at for 5 in topology of GlyR β and βΔ7 predicted to for The prediction of transmembrane a A. B. G. J. Mol. Biol. 2001; PubMed Scopus Google Scholar, G. A. Proc. Mol. Biol. 1998; Google and the protein B. G. J. Res. 2004; PubMed Scopus Google Scholar). of GlyR Expression in of this the of GlyR subunit transcripts in cells, as in spinal cord of The of cells were astrocytes as showed as by F. Mulhardt C. A. Becker C.M. H. J. Neurochem. PubMed Scopus Google Scholar, K. F. G. K. M. H. C. J. Neurosci. 23: PubMed Google Scholar). of cells for cells in cells we also a of and we the of in were by the in the and RNA by to the with GlyR detected the expression of cDNA of of as from the GlyR β subunit cDNA and cDNA of the of a novel variant of the GlyR β subunit exon This novel variant is GlyR from the βΔ7 exon 7 a from the of the large extracellular TM1 and the intracellular loop TM1 and TM2 to the first four amino acid to TM2 of the polypeptide variant encoded by the βΔ7 predicted a where TM1 and the loop TM1 and TM2 were a dramatic change in subunit topology and four positions of the amino to the TM2 were also were for a of TM2 Rather, prediction of B. G. J. Res. 2004; PubMed Scopus Google that the amino acid of the TM2 for the of the N-terminal domain that are by exon 7 to of exon the of the TM2 positions from to the of the acetylcholine-binding N-terminal domain and (4Brejc K. van Dijk W.J. Klaassen R.V. Schuurmans M. van Der Oost J. Smit A.B. Sixma T.K. Nature. 2001; 411: 269-276Crossref PubMed Scopus (1580) Google Scholar, J. R. S. A. G. Betz H. Laube B. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). the ion channel pore of the Cys-loop receptor subunits is in the βΔ7 we the into the expression In β and βΔ7 were generated N-terminal by and of β in of the of the β subunit variants to spinal cord cerebral and of adult high of the novel βΔ7 splice and a for this In adult spinal cord the for the β of βΔ7 in and adult central nervous system no significant developmental with the of β subunit transcripts present in astrocytes and from the mouse central nervous system the of the β subunit to the β and the variant exon 7 In the βΔ7 the β variant in spinal cord In Expression of the βΔ7 is from and spinal and were for of the β subunit and the splice variant βΔ7 the GlyR β we detected antigen of in cortex, spinal and to βΔ7 The of the βΔ7 not from the full-length β As from Endo the not and forms of the full-length β variant. the Endo were in a of the of βΔ7 from the β we generated a the and that is of the variant. In from cells, the the splice not the full-length β subunit In from mouse liver, a the of and of splice of full-length β subunit antigen did not the for the of Expression of the GlyR β and topological of βΔ7 predicted a of structural that are for transmembrane of Cys-loop receptors of the nicotinic acetylcholine receptor superfamily J. R. S. A. G. Betz H. Laube B. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). we the βΔ7 polypeptide into the plasma membrane. this βΔ7 polypeptide in the and of α1 and its by intracellular and protein were by with the α1 subunit of GlyR, detectable by detected in the intracellular and the The anchor protein of the GlyR complex, gephyrin, as a for the of protein from extracellular protein studies N. C. A. Kuhse J. G. Betz H. EMBO J. 1999; PubMed Scopus Google Scholar, Rev. 2004; PubMed Scopus Google showed that plasma of the GlyR β subunit a formation with ligand binding α subunits. a and intracellular expression for β and βΔ7 of the of As the amino acid of the β subunit extracellular this heterogeneity may to and that the β subunit antigen of variants is at the in of β variants with the α1 subunit did not the of the of the β and βΔ7 of the subunit variants β and βΔ7 into the plasma of cells also by 5, and As in cells the of protein in intracellular that of β protein The of β that a large of the intracellular β and βΔ7 variants were in the with by co-expression with GlyR β and extracellular domain and which may account for the polypeptide heterogeneity cells were in the of of formation of the In cells, the the forms of the β and βΔ7 the the β and βΔ7 also by of the to Endo H. protein were with Endo H, the of βΔ7 with of the polypeptide of βΔ7 with the α1 and of GlyRs at the postsynaptic of a motif the TM3–4 loop of the β subunit with the anchor protein gephyrin G. Kirsch J. Betz H. Langosch D. Neuron. 1995; 15: 563-572Abstract Full Text PDF PubMed Scopus (350) Google Scholar). formation of complexes in cells, βΔ7 polypeptide in studies co-expression with the α1 subunit and gephyrin the of β βΔ7 significant of polypeptide and gephyrin were data that the βΔ7 its altered transmembrane is to protein complexes with the α1 subunit and gephyrin. a of of the β subunit, a to the which is from α1 I. T. Langosch D. J. Betz H. EMBO J. 11: PubMed Scopus Google Scholar). cells with α1 subunit cDNA to with the formation of α1 and Despite the of glycine were of the full-length β subunit and However, were by from the in α1 receptor and The of receptor complexes and were with α1 the formation of protein complexes the novel subunit βΔ7 did not the of to the ion channel data that the ion channel pore is and by α1 subunits. This is with the structural prediction that the of exon 7 to the of a pore domain in Here, we that the GlyR β subunit is in and extraneural tissues. with the β subunit variant in adult spinal cord and cortex, the novel splice variant βΔ7 lacks exon to a of amino In the full-length subunit the positions a of the N-terminal domain as as the transmembrane domain the intracellular loop TM1 and and the first four amino of the pore forming GlyRs are by α subunit expression of β subunits has not been to in the formation of (10Grenningloh G. Pribilla I. Prior P. Multhaup G. Beyreuther K. Taleb O. Betz H. Neuron. 1990; 4: 963-970Abstract Full Text PDF PubMed Scopus (203) Google Scholar). As from in situ hybridization (11Malosio M.L. Marqueze-Pouey B. Kuhse J. Betz H. EMBO J. 1991; 10: 2401-2409Crossref PubMed Scopus (456) Google Scholar), GlyR α and β subunit a in the central nervous system, were α subunit transcripts in spinal cord and In β subunit is highly throughout the central nervous system, regions that a significant α subunit (11Malosio M.L. Marqueze-Pouey B. Kuhse J. Betz H. EMBO J. 1991; 10: 2401-2409Crossref PubMed Scopus (456) Google Scholar). the of the expression of the β subunit is not that this subunit also in non-neuronal cells, and F. Mulhardt C. A. Becker C.M. H. J. Neurochem. PubMed Scopus Google Scholar). the the subunit variant βΔ7 highly in cells and non-neuronal in the the Glrb the variant βΔ7 found in a of cells and tissues. were the a in of the extracellular during S. N. T. H. T. 2004; PubMed Scopus Google Scholar). The splice variant βΔ7 highly transcribed in cerebral and extraneural and liver, detectable in spinal splicing of β subunit into the β and βΔ7 variant no for a developmental This from the developmental of GlyR α subunit variants in the central nervous system (11Malosio M.L. Marqueze-Pouey B. Kuhse J. Betz H. EMBO J. 1991; 10: 2401-2409Crossref PubMed Scopus (456) Google Scholar, Rev. 2004; PubMed Scopus Google Scholar, H. Trends Neurosci. 1991; Full Text PDF PubMed Scopus Google Scholar). expression of central nervous system may not to also from a The is a of splicing that to the of GlyR variants in A. J. 2002; PubMed Scopus Google Scholar). may also to the of β of the GlyR splice variant βΔ7 predicted a topology of this Cys-loop receptor four transmembrane of the βΔ7 variant predicted In the in the extracellular N-terminal domain that are of the GlyR (4Brejc K. van Dijk W.J. Klaassen R.V. Schuurmans M. van Der Oost J. Smit A.B. Sixma T.K. Nature. 2001; 411: 269-276Crossref PubMed Scopus (1580) Google Scholar), are in the splice variant This in predicted transmembrane topology to the the βΔ7 variant is into a polypeptide that and into GlyR ion channel complexes. As detectable in the mouse central nervous system in of the βΔ7 variant with a β subunit antigen of that this splice variant is in cerebral and extraneural tissues. GlyRs are ion channel protein complexes with a subunit of where the β subunit to the formation of the ligand binding at its to the α subunit J. R. S. A. G. Betz H. Laube B. Neuron. 2005; Full Text Full Text PDF PubMed Scopus Google Scholar). In Cys-loop receptors, binding is to of the N-terminal extracellular regions of in a of from the N. PubMed Scopus Google Scholar). The amino acid positions to the ligand binding are not by the of prediction that the amino from the of TM2 amino forming the of the N-terminal domain of the full-length β from into a are also from A. Nat. Biol. 2005; 7: PubMed Scopus Google Scholar). The of the amino acid from TM2 into the of the N-terminal domain the of the ion channel domain. the novel subunit variant as as the β were into the plasma of cells, in the of the ligand binding α1 with a expression of the βΔ7 its assembly were from of the full-length GlyR β In the β subunit polypeptide with the ligand binding GlyR α subunit and the postsynaptic anchor gephyrin. The protein for of glycine and receptors G. Kirsch J. Betz H. Langosch D. Neuron. 1995; 15: 563-572Abstract Full Text PDF PubMed Scopus (350) Google Scholar, J. Betz H. J. Neurosci. 1995; 15: PubMed Google Scholar, J. G. Betz H. Mol. Neurosci. 8: Scopus Google Scholar). By a by gephyrin, receptors are to the postsynaptic M. Betz H. J. 2000; Scopus Google Scholar). Likewise, βΔ7 polypeptide a with the α1 subunit polypeptide and gephyrin, as from with a βΔ7 This with the protein gephyrin also that the TM3–4 loop The of exon 7 not the assembly of GlyR protein with the of N. C. A. Kuhse J. G. Betz H. EMBO J. 1999; PubMed Scopus Google Scholar), amino acid in the highly N-terminal regions that are not by the βΔ7 the of complexes to the of β transcripts the of GlyR β subunit the of the βΔ7 polypeptide In to the β subunit, which to GlyR ion D. Thomas L. Betz H. Proc. Natl. Acad. Sci. U. S. A. 1988; 85: 7394-7398Crossref PubMed Scopus (309) Google Scholar, I. T. Langosch D. J. Betz H. EMBO J. 11: PubMed Scopus Google Scholar, J.L. J. Neurochem. 2001; PubMed Scopus Google Scholar), data that βΔ7 is not to ion channel properties. the predicted of βΔ7 a GlyR subunit variant that is no to a channel Rather, βΔ7 may as subunit of the GlyR complex, to the formation of protein complexes and In addition to classical as ligand-gated of the studies expression of GlyR A. A. H. J. Neurosci. 1995; 7: PubMed Scopus Google and receptors 1994; 11: PubMed Scopus (93) Google in astrocytes and to a of synaptic of these cells, ligand-gated ion been to in as of K. J. PubMed Google Scholar), A. A. 2001; PubMed Scopus Google Scholar), and B. J.B. S. 2000; PubMed Scopus Google Scholar). as of gephyrin, GlyR β variants may also contribute to the of the ion channel function (11Malosio M.L. Marqueze-Pouey B. Kuhse J. Betz H. EMBO J. 1991; 10: 2401-2409Crossref PubMed Scopus (456) Google Scholar, M. Betz H. Trends Neurosci. 2000; 23: Full Text Full Text PDF PubMed Scopus (225) Google Scholar, M.I. Harvey K. H. L. J. K. F. Owen M.J. Harvey R.J. Snell R.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). In addition to the splice variants of the GlyR β subunit pathological alterations in GlyR β splicing the human neurological disorder hyperekplexia and the mutant of the In a of hyperekplexia with a compound of the a splice found to cause a of exon 5 from β subunit transcripts (16Rees M.I. Lewis T.M. Kwok J.B. Mortier G.R. Govaert P. Snell R.G. Schofield P.R. Owen M.J. Hum. Mol. Genet. 2002; 11: 853-860Crossref PubMed Google Scholar). In of a element into intron 5 of the Glrb results in a dramatic reduction in full-length β transcripts C. Fischer M. Gass P. Simon-Chazottes D. Guenet J.L. Kuhse J. Betz H. Becker C.M. Neuron. 1994; 13: 1003-1015Abstract Full Text PDF PubMed Scopus (170) Google Scholar, C.M. Schmieden V. P. U. Betz H. Neuron. 8: Full Text PDF PubMed Scopus Google Scholar), a of GlyRs from spinal cord and the of the GlyR β subunit for a assembly and of GlyRs in has that alternative splicing to the subtype heterogeneity of receptors in the central nervous and for during the of this and for receptor and are for and Weber and

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