Skip to main content

Advertisement

SpringerLink
Log in

Type-1, but Not Type-5, Metabotropic Glutamate Receptors are Coupled to Polyphosphoinositide Hydrolysis in the Retina

  • Original Paper
  • Published:
Neurochemical Research Aims and scope Submit manuscript

Abstract

mGlu1 and mGlu5 metabotropic glutamate receptors are expressed in the vertebrate retina, and are co-localized in some retinal neurons. It is believed that both receptors are coupled to polyphosphoinositide (PI) hydrolysis in the retina and their function may diverge in some cells because of a differential engagement of downstream signaling molecules. Here, we show that it is only the mGlu1 receptor that is coupled to PI hydrolysis in the retina. We used either bovine retinal slices or intact mouse retinas challenged with the mixed mGlu1/5 receptor agonist, DHPG. In both models, DHPG-stimulated PI hydrolysis was abrogated by the selective mGlu1 receptor antagonist, JNJ16259685, but was insensitive to the mGlu5 receptor antagonist, MPEP. In addition, the PI response to DHPG was unchanged in the retina of mGlu5−/− mice but was abolished in the retina of crv4 mice lacking mGlu1 receptors. Stimulation of the mitogen-activated protein kinase pathway by DHPG in intact mouse retinas were also entirely mediated by mGlu1 receptors. Our data provide the first example of a tissue in which a biochemically detectable PI response is mediated by mGlu1, but not mGlu5, receptors. Hence, bovine retinal slices might be used as a model for the functional screening of mGlu1 receptor ligands. In addition, the mGlu1 receptor caters the potential as a drug target in the experimental treatment of degenerative disorders of the retina.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Yang XL (2004) Characterization of receptors for glutamate and GABA in retinal neurons. Prog Neurobiol 73:127–150

    Article  CAS  PubMed  Google Scholar 

  2. Dhingra A, Vardi N (2012) mGlu receptors in the retina—WIREs membrane transport and signalling. Wiley Interdiscip Rev Membr Transp Signal 1:641–653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Nicoletti F, Bockaert J, Collingridge GL, Conn PJ, Ferraguti F, Schoepp DD, Wroblewski JT, Pin PJ (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ito I, Kohda A, Tanabe S, Hirose E, Hayashi M, Mitsunaga S, Sugiyama H (1992) 3,5-Dihydroxyphenylglycine: a potent agonist of metabotropic glutamate receptors. NeuroReport 3:1013–1016

    Article  CAS  PubMed  Google Scholar 

  5. Schoepp DD, Goldsworthy J, Johnson BG, Salhoff CR, Baker SR (1994) 3,5-Dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked metabotropic glutamate receptors in the rat hippocampus. J Neurochem 63:769–772

    Article  CAS  PubMed  Google Scholar 

  6. Dryja TP, McGee TL, Berson EL, Fishman GA, Sandberg MA, Alexander KR, Derlacki DJ, Rajagopalan AS (2005) Night blindness and abnormal cone electroretinogram ON responses in patients with mutations in the GRM6 gene encoding mGluR6. Proc Natl Acad Sci USA 102:4884–4889

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Zeitz C, van Genderen M, Neidhardt J, Luhmann UF, Hoeben F, Forster U, Wycisk K, Mátyás G, Hoyng CB, Riemslag F, Meire F, Cremers FP, Berger W (2005) Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Invest Ophthalmol Vis Sci 46:4328–4335

    Article  PubMed  Google Scholar 

  8. O’Connor E, Allen LE, Bradshaw K, Boylan J, Moore AT, Trump D (2006) Congenital stationary night blindness associated with mutations in GRM6 encoding glutamate receptor mGluR6. Br J Ophthalmol 90:653–654

    Article  PubMed  PubMed Central  Google Scholar 

  9. Scherer SW, Soder S, Duvoisin RM, Huizenga JJ, Tsui LC (1997) The human metabotropic glutamate receptor 8 (GRM8) gene: a disproportionately large gene located at 7q31.3–q32.1. Genomics 44:232–236

    Article  CAS  PubMed  Google Scholar 

  10. Bruno V, Battaglia G, Copani A, D’Onofrio M, Di Iorio P, De Blasi A, Melchiorri D, Flor PJ, Nicoletti F (2001) Metabotropic glutamate receptor subtypes as targets for neuroprotective drugs. J Cereb Blood Flow Metab 21:1013–1033

    Article  CAS  PubMed  Google Scholar 

  11. Dyka FM, May CA, Enz R (2004) Metabotropic glutamate receptors are differentially regulated under elevated intraocular pressure. J Neurochem 90:190–202

    Article  CAS  PubMed  Google Scholar 

  12. Koulen P, Kuhn R, Wassle H, Brandstätter JH (1997) Group I metabotropic glutamate receptors mGluR1α and mGluR5a: localization in both synaptic layers of the rat retina. J Neurosci 17:2200–2211

    CAS  PubMed  Google Scholar 

  13. Brandstätter JH, Koulen P, Wässle H (1998) Diversity of glutamate receptors in the mammalian retina. Vis Res 38:1385–1397

    Article  PubMed  Google Scholar 

  14. Conti V, Aghaie A, Cilli M, Martin N, Caridi G, Musante L, Candiano G, Castagna M, Fairen A, Ravazzolo R, Guenet JL, Puliti A (2006) crv4, a mouse model for human ataxia associated with kyphoscoliosis caused by an mRNA splicing mutation of the metabotropic glutamate receptor 1 (Grm1). Int J Mol Med 18:593–600

    CAS  PubMed  Google Scholar 

  15. Nicoletti F, Iadarola MJ, Wroblewski JT, Costa E (1986) Excitatory amino acid recognition sites coupled with inositol phospholipid metabolism: developmental changes and interaction with alpha 1-adrenoceptors. Proc Natl Acad Sci USA 83:1931–1935

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275

    CAS  PubMed  Google Scholar 

  17. Sacaan AI, Santori EM, Rao TS (1998) (S)-4-Carboxy-3-hydroxyphenylglycine activates phosphatidyl inositol linked metabotropic glutamate receptors in different brain regions of the neonatal rat. Neurochem Int 32:77–85

    Article  CAS  PubMed  Google Scholar 

  18. Gasparini F, Lingenhöhl K, Stoehr N, Flor PJ, Heinrich M, Vranesic I, Biollaz M, Allgeier H, Heckendorn R, Urwyler S, Varney MA, Johnson EC, Hess SD, Rao SP, Sacaan AI, Santori EM, Veliçelebi G, Kuhn R (1999) 2-Methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503

    Article  CAS  PubMed  Google Scholar 

  19. Lavreysen H, Wouters R, Bischoff F, Nóbrega Pereira S, Langlois X, Blokland S, Somers M, Dillen L, Lesage AS (2004) JNJ16259685, a highly potent, selective and systemically active mGlu1 receptor antagonist. Neuropharmacology 47:961–972

    Article  CAS  PubMed  Google Scholar 

  20. Sen M, Gleason E (2006) Immunolocalization of metabotropic glutamate receptors 1 and 5 in the synaptic layers of the chicken retina. Vis Neurosci 23:221–231

    Article  PubMed  Google Scholar 

  21. Euler T, Wässle H (1998) Different contributions of GABAA and GABAC receptors to rod and cone bipolar cells in a rat retinal slice preparation. J Neurophysiol 79:1384–1395

    CAS  PubMed  Google Scholar 

  22. Hoffpauir BK, Gleason EL (2002) Activation of mGluR5 modulates GABA(A) receptor function in retinal amacrine cells. J Neurophysiol 88:1766–1776

    CAS  PubMed  Google Scholar 

  23. Sosa R, Hoffpauir B, Rankin ML, Bruch RC, Gleason EL (2002) Metabotropic glutamate receptor 5 and calcium signaling in retinal amacrine cells. J Neurochem 81:973–983

    Article  CAS  PubMed  Google Scholar 

  24. Vigh J, Lasater EM (2003) Intracellular calcium release resulting from mGluR1 receptor activation modulates GABAA currents in wide-field retinal amacrine cells: a study with caffeine. Eur J Neurosci 17:2237–2248

    Article  PubMed  Google Scholar 

  25. Vigh J, Li GL, Hull C, von Gersdorff H (2005) Long-term plasticity mediated by mGluR1 at a retinal reciprocal synapse. Neuron 46:469–482

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rothe T, Bigl V, Grantyn R (1994) Potentiating and depressant effects of metabotropic glutamate receptor agonists on high-voltage-activated calcium currents in cultured retinal ganglion neurons from postnatal mice. Pflugers Arch 426:161–170

    Article  CAS  PubMed  Google Scholar 

  27. Akopian A, Witkovsky P (1996) Activation of metabotropic glutamate receptors decreases a high-threshold calcium current in spiking neurons of the Xenopus retina. Vis Neurosci 13:549–557

    Article  CAS  PubMed  Google Scholar 

  28. Ji M, Miao Y, Dong L-D, Chen J, Mo X-F, Jiang S-X, Sun X-H, Yang X-L, Wang Z (2012) Group I mGluR-mediated inhibition of Kir channels contributes to retinal Muller cell gliosis in a rat chronic ocular hypertension model. J Neurosci 32:12744–12755

    Article  CAS  PubMed  Google Scholar 

  29. Kawabata S, Tsutsumi R, Kohara A, Yamaguchi T, Nakanishi S, Okada M (1996) Control of calcium oscillations by phosphorylation of metabotropic glutamate receptors. Nature 383:89–92

    Article  CAS  PubMed  Google Scholar 

  30. Osborne NN (1990) Stimulatory and inhibitory actions of excitatory amino acids on inositol phospholipid metabolism in rabbit retina evidence for a specific quisqualate receptor subtype associated with neurones. Exp Eye Res 50:397–405

    Article  CAS  PubMed  Google Scholar 

  31. Puliti A, Rossi PI, Caridi G, Corbelli A, Ikehata M, Armelloni S, Li M, Zennaro C, Conti V, Vaccari CM, Cassanello M, Calevo MG, Emionite L, Ravazzolo R, Rastaldi MP (2011) Albuminuria and glomerular damage in mice lacking the metabotropic glutamate receptor 1. Am J Pathol 178:1257–1269

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Nicoletti F, Bruno V, Ngmba R, Gradini R, Battaglia G (2015) Metabotropic glutamate receptors as drug targets: What’s new? Curr Opin Pharmacol 20:89–94

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. I.R.C.C.S. Neuromed, Pozzilli, IS, Italy

    Maria Rosaria Romano, Luisa Di Menna, Pamela Scarselli, Giada Mascio, Michele Madonna, Serena Notartomaso, Valeria Bruno, Giuseppe Battaglia & Ferdinando Nicoletti

  2. Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DiNOGMI), University of Genoa, Genoa, Italy

    Aldamaria Puliti

  3. U.O.C. Genetica Medica, Istituto Giannina Gaslini, Genoa, Italy

    Aldamaria Puliti

  4. Department of Physiology and Pharmacology, University Sapienza, Rome, Italy

    Valeria Bruno & Ferdinando Nicoletti

Authors
  1. Maria Rosaria Romano
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Luisa Di Menna
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Pamela Scarselli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giada Mascio
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michele Madonna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Serena Notartomaso
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Aldamaria Puliti
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Valeria Bruno
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Battaglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ferdinando Nicoletti
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ferdinando Nicoletti.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Romano, M.R., Di Menna, L., Scarselli, P. et al. Type-1, but Not Type-5, Metabotropic Glutamate Receptors are Coupled to Polyphosphoinositide Hydrolysis in the Retina. Neurochem Res 41, 924–932 (2016). https://doi.org/10.1007/s11064-015-1775-y

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11064-015-1775-y

Keywords

Search

Navigation