Gephyrin

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Gephyrin
Protein GPHN PDB 1ihc.png
PDB rendering based on 1ihc.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols GPHN ; GEPH; GPH; GPHRYN; HKPX1; MOCODC
External IDs OMIM603930 MGI109602 HomoloGene10820 GeneCards: GPHN Gene
EC number 2.10.1.1, 2.7.7.75
RNA expression pattern
PBB GE GPHN 220773 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 10243 268566
Ensembl ENSG00000171723 ENSMUSG00000047454
UniProt Q9NQX3 Q8BUV3
RefSeq (mRNA) NM_001024218 NM_145965
RefSeq (protein) NP_001019389 NP_666077
Location (UCSC) Chr 14:
66.97 – 67.65 Mb
Chr 12:
78.23 – 78.68 Mb
PubMed search [1] [2]

Gephyrin is a 93kDa multi-functional protein that is a component of the postsynaptic protein network of inhibitory synapses. It consists of 3 domains: N terminal G domain, C terminal E domain, and a large unstructured linker domain which connects the two. Although there are structures available for trimeric G and dimeric E domains, there is no structure available for the full length protein, which may be due to the large unstructured region which makes the protein hard to crystallize. But a recent study of the full length gephyrin by small-angle X-ray scattering shows that it predominantly forms trimers, and that because of its long linker region, it can exist in either a compact state or either of two extended states.[1]

Positive antibody staining for gephyrin at a synapse is consistent with the presence of glycine and/or GABAA receptors. Nevertheless, some exceptions can occur like in neurons of Dorsal Root Ganglions where gephyrin is absent despite the presence of GABAA receptors.[2] Gephyrin is considered a major scaffolding protein at inhibitory synapses, analogous in its function to that of PSD-95 at glutamatergic synapses.[3][4] Gephyrin was identified by its interaction with the glycine receptor, the main receptor protein of inhibitory synapses in the spinal cord and brainstem. In addition to its interaction with the glycine receptor, recent publications have shown that gephyrin also interacts with the intracellular loop between the transmembrane helices TM3 and TM4 of alpha and beta subunits of the GABAA receptor.[5]

Gephyrin displaces GABA receptors from the GABARAP/P130 complex, then brings the receptors to the synapse.[6] Once at the synapse, the protein binds to collybistin[7] and neuroligin 2.[8] In cells, gephyrin appears to form oligomers of at least three subunits. Several splice variants have been described that prevent this oligomerization without influencing the affinity for receptors. They nevertheless affect the composition of inhibitory synapses and can even play a role in diseases like epilepsy.[9]

Humans with temporal lobe epilepsy have been found to have abnormally low levels of gephyrin in their temporal lobes.[10] In animal models, a total lack of gephyrin results in stiff muscles and death immediately after birth. Stiff muscles are also a symptom of startle disease, that can be caused by a mutation in the gephyrin gene. And if a person produces auto-antibodies against gephyrin, this can even result in stiff person syndrome.[9]

The gephyrin protein is also required during molybdenum cofactor assembly for insertion of molybdenum.[11]

References[edit]

  1. ^ Sander, B; Tria, G; Shkumatov, AV; Kim, EY; Grossmann, JG; Tessmer, I; Svergun, DI; Schindelin, H (Oct 2013). "Structural characterization of gephyrin by AFM and SAXS reveals a mixture of compact and extended states.". Acta crystallographica. Section D, Biological crystallography 69 (Pt 10): 2050–60. doi:10.1107/S0907444913018714. PMID 24100323. 
  2. ^ Lorenzo LE, Godin AG, Wang F, St-Louis M, Carbonetto S, Wiseman PW, Ribeiro-da-Silva A, De Koninck Y (June 2014). "Gephyrin Clusters Are Absent from Small Diameter Primary Afferent Terminals Despite the Presence of GABAA Receptors". J. Neurosci. 34 (24): 8300–17. doi:10.1523/JNEUROSCI.0159-14.2014. PMID 24920633. 
  3. ^ Giesemann T, Schwarz G, Nawrotzki R, Berhörster K, Rothkegel M, Schlüter K, Schrader N, Schindelin H, Mendel RR, Kirsch J, Jockusch BM (September 2003). "Complex formation between the postsynaptic scaffolding protein gephyrin, profilin, and Mena: a possible link to the microfilament system". J. Neurosci. 23 (23): 8330–9. PMID 12967995. 
  4. ^ Ehrensperger MV, Hanus C, Vannier C, Triller A, Dahan M (May 2007). "Multiple association states between glycine receptors and gephyrin identified by SPT analysis". Biophys. J. 92 (10): 3706–18. doi:10.1529/biophysj.106.095596. PMC 1853151. PMID 17293395. 
  5. ^ Maric HM, Mukherjee J, Tretter V, Moss SJ, Schindelin H (December 2011). "Gephyrin-mediated γ-aminobutyric acid type A and glycine receptor clustering relies on a common binding site". J. Biol. Chem. 286 (49): 42105–14. doi:10.1074/jbc.M111.303412. PMC 3234978. PMID 22006921. 
  6. ^ Thiriet, Marc (2013). Intracellular Signaling Mediators in the Circulatory and Ventilatory Systems. New York, NY: Springer New York. p. 605. ISBN 978-1-4614-4370-4. 
  7. ^ Kins S, Betz H, Kirsch J (January 2000). "Collybistin, a newly identified brain-specific GEF, induces submembrane clustering of gephyrin". Nat. Neurosci. 3 (1): 22–9. doi:10.1038/71096. PMID 10607391. 
  8. ^ Poulopoulos A, Aramuni G, Meyer G, Soykan T, Hoon M, Papadopoulos T, Zhang M, Paarmann I, Fuchs C, Harvey K, Jedlicka P, Schwarzacher SW, Betz H, Harvey RJ, Brose N, Zhang W, Varoqueaux F (September 2009). "Neuroligin 2 drives postsynaptic assembly at perisomatic inhibitory synapses through gephyrin and collybistin". Neuron 63 (5): 628–42. doi:10.1016/j.neuron.2009.08.023. PMID 19755106. 
  9. ^ a b Tretter V, Mukherjee J, Maric HM, Schindelin H, Sieghart W, Moss SJ (2012). "Gephyrin, the enigmatic organizer at GABAergic synapses". Front Cell Neurosci 6: 23. doi:10.3389/fncel.2012.00023. PMC 3351755. PMID 22615685. 
  10. ^ Fang M, Shen L, Yin H, Pan YM, Wang L, Chen D, Xi ZQ, Xiao Z, Wang XF, Zhou SN (October 2011). "Downregulation of gephyrin in temporal lobe epilepsy neurons in humans and a rat model". Synapse 65 (10): 1006–14. doi:10.1002/syn.20928. PMID 21404332. 
  11. ^ Reiss J, Johnson JL (June 2003). "Mutations in the molybdenum cofactor biosynthetic genes MOCS1, MOCS2, and GEPH". Hum. Mutat. 21 (6): 569–76. doi:10.1002/humu.10223. PMID 12754701.