Receptors, gephyrin and gephyrin‐associated proteins: novel insights into the assembly of inhibitory postsynaptic membrane specializations

The synaptic localization of ion channel receptors is essential for efficient synaptic trans‐mission and the precise regulation of diverse neuronal functions, such as signal integration and synaptic plasticity. Emerging evidence points to an important role of cytoskeleton‐associated proteins that assemble receptors and components of the subsynaptic machinery at postsynaptic membrane specializations. This article reviews interactions of inhibitory postsynaptic neurotransmitter receptors with the receptor anchoring protein gephyrin and intracellular components involved in downstream signalling and/or control of signal transduction processes. The presently available data suggest a central synaptic organizer function for gephyrin in inhibitory postsynaptic membrane assembly and stabilization.

[1]  J. Kirsch,et al.  Incorporation of a gephyrin‐binding motif targets NMDA receptors to gephyrin‐rich domains in HEK 293 cells , 1999, The European journal of neuroscience.

[2]  W. J. Grimes.  Glycosyltransferase and sialic acid levels of normal and transformed cells. , 1973, Biochemistry.

[3]  C. Becker,et al.  Glycine receptor heterogeneity in rat spinal cord during postnatal development. , 1988, The EMBO journal.

[4]  J. Kirsch,et al.  Widespread expression of gephyrin, a putative glycine receptor-tubulin linker protein, in rat brain , 1993, Brain Research.

[5]  A. Craig,et al.  Clustering of Gephyrin at GABAergic but Not Glutamatergic Synapses in Cultured Rat Hippocampal Neurons , 1996, The Journal of Neuroscience.

[6]  H. Wässle,et al.  Colocalization of gephyrin and GABAA‐receptor subunits in the rat retina , 1995, The Journal of comparative neurology.

[7]  J. Kirsch,et al.  Neuraxin corresponds to a C‐terminal fragment of microtubule‐associated protein 5 (MAP5) , 1990, FEBS letters.

[8]  S. Snyder,et al.  Interaction of RAFT1 with gephyrin required for rapamycin-sensitive signaling. , 1999, Science.

[9]  M. Falasca,et al.  Specificity and Promiscuity in Phosphoinositide Binding by Pleckstrin Homology Domains* , 1998, The Journal of Biological Chemistry.

[10]  J. Kirsch,et al.  The inhibitory glycine receptor: architecture, synaptic localization and molecular pathology of a postsynaptic ion-channel complex , 1995, Current Opinion in Neurobiology.

[11]  M. Giustetto,et al.  Localization of the clustering protein gephyrin at GABAergic synapses in the main olfactory bulb of the rat , 1998, The Journal of comparative neurology.

[12]  A. Triller,et al.  Dendritic and Postsynaptic Localizations of Glycine Receptor α Subunit mRNAs , 1997, The Journal of Neuroscience.

[13]  A. Triller,et al.  Strychnine-sensitive stabilization of postsynaptic glycine receptor clusters. , 1998, Journal of cell science.

[14]  H. Rohrer,et al.  Glycine Receptors in Cultured Chick Sympathetic Neurons are Excitatory and Trigger Neurotransmitter Release , 1997, The Journal of physiology.

[15]  Bernhard Lüscher,et al.  Postsynaptic clustering of major GABAA receptor subtypes requires the γ2 subunit and gephyrin , 1998, Nature Neuroscience.

[16]  J. Schlessinger,et al.  PH Domains: Diverse Sequences with a Common Fold Recruit Signaling Molecules to the Cell Surface , 1996, Cell.

[17]  W. Sieghart,et al.  Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[18]  J. Brandstätter,et al.  Loss of Postsynaptic GABAA Receptor Clustering in Gephyrin-Deficient Mice , 1999, The Journal of Neuroscience.

[19]  O. Steward,et al.  Lamina-Specific Synaptic Activation Causes Domain-Specific Alterations in Dendritic Immunostaining for MAP2 and CAM Kinase II , 1999, The Journal of Neuroscience.

[20]  F. Pfeiffer,et al.  Purification by affinity chromatography of the glycine receptor of rat spinal cord. , 1982, The Journal of biological chemistry.

[21]  J. Kirsch,et al.  Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin , 2000, Nature Neuroscience.

[22]  Oswald Steward,et al.  Synaptic Activation Causes the mRNA for the IEG Arc to Localize Selectively near Activated Postsynaptic Sites on Dendrites , 1998, Neuron.

[23]  A. Triller,et al.  Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons , 1993, Nature.

[24]  M. Colledge,et al.  Signals mediating ion channel clustering at the neuromuscular junction , 1998, Current Opinion in Neurobiology.

[25]  D. Langosch,et al.  The 93-kDa glycine receptor-associated protein binds to tubulin. , 1991, Journal of Biological Chemistry.

[26]  M. Tohyama,et al.  Localization of glycine receptors in the rat central nervous system: An immunocytochemical analysis using monoclonal antibody , 1988, Neuroscience.

[27]  H. Korn,et al.  gamma-Aminobutyric acid-containing terminals can be apposed to glycine receptors at central synapses , 1987, The Journal of cell biology.

[28]  L. Rubin,et al.  Components of Torpedo electric organ and muscle that cause aggregation of acetylcholine receptors on cultured muscle cells , 1984, The Journal of cell biology.

[29]  H. Betz.  Gephyrin, a major player in GABAergic postsynaptic membrane assembly? , 1998, Nature Neuroscience.

[30]  R. Wanders,et al.  Molybdenum cofactor deficiency and isolated sulfite oxidase deficiency (ch.128) , 2001 .

[31]  T. Sasaki,et al.  Bni1p and Bnr1p: downstream targets of the Rho family small G‐proteins which interact with profilin and regulate actin cytoskeleton in Saccharomyces cerevisiae , 1997, The EMBO journal.

[32]  G. Meyer,et al.  Synaptic Targeting of Ionotropic Neurotransmitter Receptors , 1996, Molecular and Cellular Neuroscience.

[33]  J. Kirsch,et al.  Glycine-receptor activation is required for receptor clustering in spinal neurons , 1998, Nature.

[34]  K. Nagahari,et al.  Derepression of E. coli trp operon on interfamilial transfer , 1977, Nature.

[35]  J. Kirsch,et al.  Distribution of Gephyrin Transcripts in the Adult and Developing Rat Brain , 1993, The European journal of neuroscience.

[36]  J. Kirsch,et al.  Targeting of Glycine Receptor Subunits to Gephyrin-Rich Domains in Transfected Human Embryonic Kidney Cells , 1995, Molecular and Cellular Neuroscience.

[37]  B. Marquèze-Pouey,et al.  Widespread expression of glycine receptor subunit mRNAs in the adult and developing rat brain. , 1991, The EMBO journal.

[38]  G. Feng,et al.  Dual requirement for gephyrin in glycine receptor clustering and molybdoenzyme activity. , 1998, Science.

[39]  N. Brandon,et al.  GABAA-receptor-associated protein links GABAA receptors and the cytoskeleton , 1999, Nature.

[40]  R. Mendel.  Molybdenum cofactor of higher plants: biosynthesis and molecular biology , 1997, Planta.

[41]  J. Theriot,et al.  Dynamic actin structures stabilized by profilin. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[42]  M. Mann,et al.  In mouse brain profilin I and profilin II associate with regulators of the endocytic pathway and actin assembly , 1998, The EMBO journal.

[43]  F. Pfeiffer,et al.  Purification and characterization of the glycine receptor of pig spinal cord. , 1985, Biochemistry.

[44]  A. Triller,et al.  Expression of Glycine Receptor α Subunits and Gephyrin in Cultured Spinal Neurons , 1996 .

[45]  D. Bredt,et al.  PDZ Proteins Organize Synaptic Signaling Pathways , 1998, Cell.

[46]  M. Kneussel,et al.  Hydrophobic Interactions Mediate Binding of the Glycine Receptor β‐Subunit to Gephyrin , 1999, Journal of neurochemistry.

[47]  C. Becker,et al.  The Mr 93,000 polypeptide of the postsynaptic glycine receptor complex is a peripheral membrane protein. , 1987, Biochemistry.

[48]  P. Jonas,et al.  Corelease of two fast neurotransmitters at a central synapse. , 1998, Science.

[49]  N. Mendell,et al.  Postsynaptic gephyrin immunoreactivity exhibits a nearly one‐to‐one correspondence with gamma‐aminobutyric acid‐like immunogold‐labeled synaptic inputs to sympathetic preganglionic neurons , 1995, The Journal of comparative neurology.

[50]  M. Koch,et al.  Increased startle responses in mice carrying mutations of glycine receptor subunit genes , 1996, Neuroreport.

[51]  S. Moss,et al.  The protein MAP-1B links GABAC receptors to the cytoskeleton at retinal synapses , 1999, Nature.

[52]  Marc Bickle,et al.  The Yeast Phosphatidylinositol Kinase Homolog TOR2 Activates RHO1 and RHO2 via the Exchange Factor ROM2 , 1997, Cell.

[53]  J. Kirsch,et al.  The postsynaptic localization of the glycine receptor-associated protein gephyrin is regulated by the cytoskeleton , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[54]  J. Benson,et al.  Postsynaptic clustering of γ-aminobutyric acid type A receptors by the γ3 subunit in vivo , 1999 .

[55]  W. Sieghart,et al.  Synaptic Control of Glycine and GABAA Receptors and Gephyrin Expression in Cultured Motoneurons , 1999, The Journal of Neuroscience.

[56]  D. Reichling,et al.  Mechanisms of GABA and glycine depolarization‐induced calcium transients in rat dorsal horn neurons. , 1994, The Journal of physiology.

[57]  J. Kirsch,et al.  Neuraxin, a novel putative structural protein of the rat central nervous system that is immunologically related to microtubule‐associated protein 5. , 1989, EMBO Journal.

[58]  M. Sheng,et al.  PDZs and Receptor/Channel Clustering: Rounding Up the Latest Suspects , 1996, Neuron.

[59]  C. Becker,et al.  Primary cultures of mouse spinal cord express the neonatal isoform of the inhibitory glycine receptor , 1989, Neuron.

[60]  L. Johnston,et al.  Analysis of RhoA-binding Proteins Reveals an Interaction Domain Conserved in Heterotrimeric G Protein β Subunits and the Yeast Response Regulator Protein Skn7* , 1998, The Journal of Biological Chemistry.

[61]  J. Kirsch.  Assembly of signaling machinery at the postsynaptic membrane , 1999, Current Opinion in Neurobiology.

[62]  Christine C. Hudson,et al.  Phosphorylation of the translational repressor PHAS-I by the mammalian target of rapamycin. , 1997, Science.

[63]  Dieter Langosch,et al.  Identification of a gephyrin binding motif on the glycine receptor β subunit , 1995, Neuron.

[64]  S. Bohlhalter,et al.  Inhibitory neurotransmission in rat spinal cord: co-localization of glycine- and GABAA-receptors at GABAergic synaptic contacts demonstrated by triple immunofluorescence staining , 1994, Brain Research.

[65]  D. Reichling,et al.  Developmental Loss of GABA‐ and Glycine‐induced Depolarization and Ca2+ Transients in Embryonic Rat Dorsal Horn Neurons in Culture , 1994, The European journal of neuroscience.

[66]  M. Rothkegel,et al.  Profilins as regulators of actin dynamics. , 1997, Biochimica et biophysica acta.

[67]  J. Reiss,et al.  The neurotransmitter receptor-anchoring protein gephyrin reconstitutes molybdenum cofactor biosynthesis in bacteria, plants, and mammalian cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[68]  T. Reid,et al.  Identification and Characterization of hPEM-2, a Guanine Nucleotide Exchange Factor Specific for Cdc42* , 1999, The Journal of Biological Chemistry.

[69]  T. Sasaki,et al.  Interactions of drebrin and gephyrin with profilin. , 1998, Biochemical and biophysical research communications.

[70]  G. Multhaup,et al.  Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein , 1992, Neuron.

[71]  H. Korn,et al.  Heterogeneous distribution of glycinergic and GABAergic afferents on an identified central neuron , 1993, The Journal of comparative neurology.