Metabotropic glutamate receptor 6
Glutamate receptor, metabotropic 6, also known as GRM6 or mGluR6, is a protein which in humans is encoded by the GRM6 gene.[5][6]
Function
[edit]L-glutamate is the major excitatory neurotransmitter in the central nervous system and activates both ionotropic and metabotropic glutamate receptors. Glutamatergic neurotransmission is involved in most aspects of normal brain function and can be perturbed in many neuropathologic conditions. The metabotropic glutamate receptors are a family of G protein-coupled receptors, that have been divided into 3 groups on the basis of sequence homology, putative signal transduction mechanisms, and pharmacologic properties. Group I includes GRM1 and GRM5 and these receptors have been shown to activate phospholipase C. Group II includes GRM2 and GRM3, while Group III includes GRM4, GRM6, GRM7 and GRM8. Group II and III receptors are linked to the inhibition of the cyclic AMP cascade but differ in their agonist selectivities.[5]
mGluR6 is specifically expressed in the retina, in a subtype of bipolar cells that depolarize in response to light, known as ON bipolar cells. These cells form synapses with photoreceptor cells, and detect the neurotransmitter glutamate via a GPCR signal transduction cascade. The glutamate receptor mGluR6 is located post-synaptically at the tips of the bipolar cell dendrites, and is responsible for initiating a signaling cascade that ultimately controls gating of the TRPM1 channel.[7][8] In human patients, mutations in the GRM6 gene are associated with congenital stationary night blindness.[9][10]
Ligands
[edit]Compounds L-AP4[11] and 1-benzyl-APDC[12] act as selective agonists of group III mGluRs and mGlu6 receptors, respectively.
A small library of photoswitchable agonists-positive allosteric modulators of mGlu6 receptors ('prosthe6') has been developed.[13] Their light-dependent (photopharmacological) activity in ON bipolar cells mimics the physiological signaling of the retina and allows restoring vision in animal models of retinal degeneration. In particular, they restore visually guided behavior in mouse models of macular degeneration and retinitis pigmentosa, and restore visual acuity in blinded zebrafish larvae.
See also
[edit]References
[edit]- 1 2 3 GRCh38: Ensembl release 89: ENSG00000113262 – Ensembl, May 2017
- 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000000617 – Ensembl, May 2017
- ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- 1 2 "Entrez Gene: GRM6 glutamate receptor, metabotropic 6".
- ↑ Hashimoto T, Inazawa J, Okamoto N, Tagawa Y, Bessho Y, Honda Y, et al. (June 1997). "The whole nucleotide sequence and chromosomal localization of the gene for human metabotropic glutamate receptor subtype 6". The European Journal of Neuroscience. 9 (6): 1226–1235. doi:10.1111/j.1460-9568.1997.tb01477.x. PMID 9215706. S2CID 25387864.
- ↑ Nakajima Y, Iwakabe H, Akazawa C, Nawa H, Shigemoto R, Mizuno N, et al. (1993). "Molecular characterization of a novel retinal metabotropic glutamate receptor mGluR6 with a high agonist selectivity for L-2-amino-4-phosphonobutyrate". The Journal of Biological Chemistry. 268 (16): 11868–11873. doi:10.1016/S0021-9258(19)50280-0. PMID 8389366.
- ↑ Masu M, Iwakabe H, Tagawa Y, Miyoshi T, Yamashita M, Fukuda Y, et al. (1995). "Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene". Cell. 80 (5): 757–765. doi:10.1016/0092-8674(95)90354-2. PMID 7889569. S2CID 17081238.
- ↑ Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, et al. (2005). "Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6". Proceedings of the National Academy of Sciences of the United States of America. 102 (13): 4884–4889. Bibcode:2005PNAS..102.4884D. doi:10.1073/pnas.0501233102. PMC 555731. PMID 15781871.
- ↑ Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, et al. (2005). "Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram". Investigative Ophthalmology & Visual Science. 46 (11): 4328–4335. doi:10.1167/iovs.05-0526. PMID 16249515.
- ↑ Thomsen C (August 1997). "The L-AP4 receptor". General Pharmacology: The Vascular System. 29 (2): 151–158. doi:10.1016/S0306-3623(96)00417-X. PMID 9251893.
- ↑ Tückmantel W, Kozikowski AP, Shaomeng W, Pshenichkin S, Wroblewski JT (1997-03-04). "Synthesis, molecular modeling, and biology of the 1-benzyl derivative of APDC-an apparent mGluR6 selective ligand". Bioorganic & Medicinal Chemistry Letters. 7 (5): 601–606. doi:10.1016/S0960-894X(97)00068-1. ISSN 0960-894X.
- ↑ Sortino R, González-Díez A, Milla-Navarro S, Martínez-Tambella J, Paleo-García V, Calatayud E, et al. (July 2026). "Restoration of Saccadic Eye Movements and Visually Guided Behavior in Ambient White Light with Photoswitchable Small Molecules". Journal of the American Chemical Society jacs.5c18611. doi:10.1021/jacs.5c18611. PMID 42454894.
Further reading
[edit]- Dhingra A, Lyubarsky A, Jiang M, Pugh EN, Birnbaumer L, Sterling P, et al. (December 2000). "The light response of ON bipolar neurons requires G[alpha]o". The Journal of Neuroscience. 20 (24): 9053–9058. doi:10.1523/JNEUROSCI.20-24-09053.2000. PMC 6773027. PMID 11124982.
- Valerio A, Ferraboli S, Paterlini M, Spano P, Barlati S (January 2001). "Identification of novel alternatively-spliced mRNA isoforms of metabotropic glutamate receptor 6 gene in rat and human retina". Gene. 262 (1–2): 99–106. doi:10.1016/S0378-1119(00)00547-3. PMID 11179672.
- Zeitz C, Forster U, Neidhardt J, Feil S, Kälin S, Leifert D, et al. (August 2007). "Night blindness-associated mutations in the ligand-binding, cysteine-rich, and intracellular domains of the metabotropic glutamate receptor 6 abolish protein trafficking". Human Mutation. 28 (8): 771–780. doi:10.1002/humu.20499. PMID 17405131. S2CID 24946081.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
| |||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||
| |||||||||||||||||||||||||||||||||||
 | This transmembrane receptor-related article is a stub. You can help Wikipedia by adding missing information. |