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Gene Review

Gphn  -  gephyrin

Rattus norvegicus

Synonyms: Gephyrin, Gph
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Disease relevance of Gphn

  • Gephyrin-(2-188) forms trimers in solution, and a sequence motif thought to be involved in molybdopterin binding is highly conserved between gephyrin and the E. coli protein [1].
  • Gephyrin is present on the postsynaptic membrane of amacrine cells and ganglion cells [2].

High impact information on Gphn

  • In hippocampal neurons, GSK3β signaling affects gephyrin phosphorylation at Ser270 to regulate formation and plasticity at GABAergic synapses [3].
  • In spinal neurons, synaptic targeting of the inhibitory glycine receptor (GlyR) depends on the expression of the anchoring protein gephyrin [4].
  • Moreover, gephyrin binds with high affinity to polymerized tubulin and has been postulated to link the GlyR to the subsynaptic cytoskeleton [5].
  • Thus, gephyrin is essential for localizing the GlyR to presumptive postsynaptic plasma membrane specializations [5].
  • Ultrastructural studies have shown that the peripheral membrane protein gephyrin, which co-purifies with the postsynaptic inhibitory glycine receptor (GlyR) upon affinity chromatography, is situated on the cytoplasmic face of glycinergic postsynaptic membranes [5].
  • This protein, named gephyrin (from the Greek gamma epsilon phi upsilon rho alpha, bridge), is thought to anchor the GlyR to subsynaptic microtubules [6].

Chemical compound and disease context of Gphn

  • The Drosophila molybdenum cofactor gene cinnamon is homologous to three Escherichia coli cofactor proteins and to the rat protein gephyrin [7].
  • Lithium Chloride is therapeutically used to treat patients with biopolar disorder; however, its mode of action has been unclear so far. Lithium affects gephyrin clustering via the GSK3β pathway and its influence on Gephyrin Ser270 phosphorylation. Lithium mediated increase in gephyrin clustering at GABAergic synapses in hippocampus (CA1 and molecular layer), is mirrored by an increased size of PSD-95 clusters in the same region [3].

Biological context of Gphn

  • In brain, at least five different gephyrin mRNAs are generated by alternative splicing [6].
  • Here, we show that full-length gephyrin is a trimer and that its proteolysis in vitro causes the spontaneous dimerization of its C-terminal region (gephyrin-E), which binds a GlyR beta-subunit-derived peptide with high and low affinity [8].
  • Binding of gephyrin to the GlyR is exclusively mediated by the E domain, and the binding site was mapped to one of its sub-domains (residues 496-654) [9].
  • Previously, we reported that gene expression for the GABA(A) receptor clustering protein gephyrin was significantly downregulated in the BLA after fear acquisition (Ressler et al., 2002) [10].
  • In the present study we intended to determine the capacity of these two splice variants to accumulate at inhibitory synaptic terminals and to colocalize with gephyrin, and to find out whether phosphorylation of Ser343 has any effect on GABAAR distribution [11].

Anatomical context of Gphn

  • In this work, seven isoforms of gephyrin were cloned from adult rat spinal cord, some of then containing new cassettes [12].
  • Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction [10].
  • Biochemical studies of the patient's fibroblasts demonstrate that gephyrin catalyzes the insertion of molybdenum into molybdopterin and suggest that this novel form of MoCo deficiency might be curable by molybdate supplementation [13].
  • Because gephyrin expression can rescue a MoCo-deficient mutation in bacteria, plants, and a murine cell line, it became clear that gephyrin also plays a role in MoCo biosynthesis [13].
  • Gephyrin is ubiquitously expressed, and was initially found in the central nervous system, where it is essential for clustering of inhibitory neuroreceptors in the postsynaptic membrane [14].

Associations of Gphn with chemical compounds

  • Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons [5].
  • Besides its structural role, gephyrin is involved in the biosynthesis of the molybdenum cofactor that is essential for all molybdenum-dependent enzymes in mammals [9].
  • These results identify the C5 splice variant of gephyrin as a factor regulating the transmitter-appropriate degree of GlyR accumulation at inhibitory synapses [15].
  • Consequently, gephyrin is not a ligand for the proline-binding motif of profilins, as suspected previously [16].
  • Many synapses showed both GABAA beta 3 and gephyrin immunoreactivity, and at most of these synapses GABA and glycine were enriched in the presynaptic axon [17].

Co-localisations of Gphn


Regulatory relationships of Gphn

  • A corresponding production of stable, carboxy-terminal gephyrin fragments of 48-50 kDa occurred within 1 min of proteolytic activation and was blocked by the selective calpain inhibitor CX295 [19].
  • Calpain-1 clips gephyrin clusters in a Ca2+ dependent mechanism to regulate plasticity at GABAergic synapses [3].
  • Simultaneous immunolabeling for gephyrin and cell-specific markers showed that granule cells and parvalbumin-positive interneurons express gephyrin [18].
  • In the rat, all neurons classified as Renshaw cells (n = 487) also contained calbindin D28k-immunoreactivity, and all calbindin D28k-immunoreactive cells located in the ventral-most region of lamina VII expressed the characteristic gephyrin labeling and morphology of Renshaw cells [20].

Other interactions of Gphn

  • Calpain-1 interaction with gephyrin is not GSK3β dependent [3].
  • PIN possesses two binding grooves, that have been shown to interact with several targets, including neuronal NO synthase, dynein intermediate chain, myosin V, the proapoptotic protein Bim, the scaffolding proteins DAP1alpha and gephyrin, and the transcription factor NRF-1 [21].
  • Variants of the receptor/channel clustering molecule gephyrin in brain: distinct distribution patterns, developmental profiles, and proteolytic cleavage by calpain [19].
  • These studies reveal an unsuspected heterogeneity in the modes of attachment of postsynaptic proteins to the cytoskeleton and support the idea that PSD-95 and gephyrin may be core scaffolding components independent of the actin or tubulin cytoskeleton [22].
  • Large, intensely stained, gephyrin-positive clusters were distributed along distinct dendrites, and most of them were positive for parvalbumin [18].
  • Furthermore, agrin immunoreactive axons were found adjacent to gephyrin, the postsynaptic glycine receptor-associated protein [23].

Analytical, diagnostic and therapeutic context of Gphn




  1. X-ray crystal structure of the trimeric N-terminal domain of gephyrin. Sola, M., Kneussel, M., Heck, I.S., Betz, H., Weissenhorn, W. J. Biol. Chem. (2001) [Pubmed]
  2. Immunocytochemical localization of glycine receptors in the mammalian retina. Grünert, U., Wässle, H. J. Comp. Neurol. (1993) [Pubmed]
  3. Regulation of GABAergic synapse formation and plasticity by GSK3beta-dependent phosphorylation of gephyrin. Tyagarajan, S.K., Ghosh, H., Yévenes, G.E., Nikonenko, I., Ebeling, C., Schwerdel, C., Sidler, C., Zeilhofer, H.U., Gerrits, B., Muller, D., Fritschy, J.M. Proc. Natl. Acad. Sci. U. S. A. (2011) [Pubmed]
  4. Glycine-receptor activation is required for receptor clustering in spinal neurons. Kirsch, J., Betz, H. Nature (1998) [Pubmed]
  5. Gephyrin antisense oligonucleotides prevent glycine receptor clustering in spinal neurons. Kirsch, J., Wolters, I., Triller, A., Betz, H. Nature (1993) [Pubmed]
  6. Primary structure and alternative splice variants of gephyrin, a putative glycine receptor-tubulin linker protein. Prior, P., Schmitt, B., Grenningloh, G., Pribilla, I., Multhaup, G., Beyreuther, K., Maulet, Y., Werner, P., Langosch, D., Kirsch, J. Neuron (1992) [Pubmed]
  7. The Drosophila molybdenum cofactor gene cinnamon is homologous to three Escherichia coli cofactor proteins and to the rat protein gephyrin. Kamdar, K.P., Shelton, M.E., Finnerty, V. Genetics (1994) [Pubmed]
  8. Structural basis of dynamic glycine receptor clustering by gephyrin. Sola, 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) [Pubmed]
  9. Biochemical characterization of the high affinity binding between the glycine receptor and gephyrin. Schrader, N., Kim, E.Y., Winking, J., Paulukat, J., Schindelin, H., Schwarz, G. J. Biol. Chem. (2004) [Pubmed]
  10. Regulation of gephyrin and GABAA receptor binding within the amygdala after fear acquisition and extinction. Chhatwal, J.P., Myers, K.M., Ressler, K.J., Davis, M. J. Neurosci. (2005) [Pubmed]
  11. Preferential accumulation of GABAA receptor gamma 2L, not gamma 2S, cytoplasmic loops at rat spinal cord inhibitory synapses. Meier, J., Grantyn, R. J. Physiol. (Lond.) (2004) [Pubmed]
  12. Functional heterogeneity of gephyrins. Meier, J., De Chaldée, M., Triller, A., Vannier, C. Mol. Cell. Neurosci. (2000) [Pubmed]
  13. A mutation in the gene for the neurotransmitter receptor-clustering protein gephyrin causes a novel form of molybdenum cofactor deficiency. Reiss, J., Gross-Hardt, S., Christensen, E., Schmidt, P., Mendel, R.R., Schwarz, G. Am. J. Hum. Genet. (2001) [Pubmed]
  14. Crystal structures of human gephyrin and plant Cnx1 G domains: comparative analysis and functional implications. Schwarz, G., Schrader, N., Mendel, R.R., Hecht, H.J., Schindelin, H. J. Mol. Biol. (2001) [Pubmed]
  15. A gephyrin-related mechanism restraining glycine receptor anchoring at GABAergic synapses. Meier, J., Grantyn, R. J. Neurosci. (2004) [Pubmed]
  16. Complex formation between the postsynaptic scaffolding protein gephyrin, profilin, and Mena: a possible link to the microfilament system. Giesemann, T., Schwarz, G., Nawrotzki, R., Berhörster, K., Rothkegel, M., Schlüter, K., Schrader, N., Schindelin, H., Mendel, R.R., Kirsch, J., Jockusch, B.M. J. Neurosci. (2003) [Pubmed]
  17. Colocalization of GABA, glycine, and their receptors at synapses in the rat spinal cord. Todd, A.J., Watt, C., Spike, R.C., Sieghart, W. J. Neurosci. (1996) [Pubmed]
  18. Distribution of the receptor-anchoring protein gephyrin in the rat dentate gyrus and changes following entorhinal cortex lesion. Simbürger, E., Plaschke, M., Kirsch, J., Nitsch, R. Cereb. Cortex (2000) [Pubmed]
  19. Variants of the receptor/channel clustering molecule gephyrin in brain: distinct distribution patterns, developmental profiles, and proteolytic cleavage by calpain. Kawasaki, B.T., Hoffman, K.B., Yamamoto, R.S., Bahr, B.A. J. Neurosci. Res. (1997) [Pubmed]
  20. Calbindin D28k expression in immunohistochemically identified Renshaw cells. Carr, P.A., Alvarez, F.J., Leman, E.A., Fyffe, R.E. Neuroreport (1998) [Pubmed]
  21. Cellulose membrane supported peptide arrays for deciphering protein-protein interaction sites: the case of PIN, a protein with multiple natural partners. Lajoix, A.D., Gross, R., Aknin, C., Dietz, S., Granier, C., Laune, D. Mol. Divers. (2004) [Pubmed]
  22. Postsynaptic scaffolds of excitatory and inhibitory synapses in hippocampal neurons: maintenance of core components independent of actin filaments and microtubules. Allison, D.W., Chervin, A.S., Gelfand, V.I., Craig, A.M. J. Neurosci. (2000) [Pubmed]
  23. Axonal targeting of agrin in cultured rat dorsal horn neurons. Escher, G., Béchade, C., Levi, S., Triller, A. J. Cell. Sci. (1996) [Pubmed]
  24. The postsynaptic localization of the glycine receptor-associated protein gephyrin is regulated by the cytoskeleton. Kirsch, J., Betz, H. J. Neurosci. (1995) [Pubmed]
  25. Dendritic and postsynaptic localizations of glycine receptor alpha subunit mRNAs. Racca, C., Gardiol, A., Triller, A. J. Neurosci. (1997) [Pubmed]
  26. Strychnine-sensitive stabilization of postsynaptic glycine receptor clusters. Lévi, S., Vannier, C., Triller, A. J. Cell. Sci. (1998) [Pubmed]
  27. A population of large lamina I projection neurons with selective inhibitory input in rat spinal cord. Puskár, Z., Polgár, E., Todd, A.J. Neuroscience (2001) [Pubmed]
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