Skip to main content
SpringerLink
Log in

Control of neuronal excitability by Group I metabotropic glutamate receptors

  • Review
  • Published:
Biophysical Reviews Aims and scope Submit manuscript

Abstract

Metabotropic glutamate (mGlu) receptors couple through G proteins to regulate a large number of cell functions. Eight mGlu receptor isoforms have been cloned and classified into three Groups based on sequence, signal transduction mechanisms and pharmacology. This review will focus on Group I mGlu receptors, comprising the isoforms mGlu1 and mGlu5. Activation of these receptors initiates both G protein-dependent and -independent signal transduction pathways. The G-protein-dependent pathway involves mainly Gαq, which can activate PLCβ, leading initially to the formation of IP3 and diacylglycerol. IP3 can release Ca2+ from cellular stores resulting in activation of Ca2+-dependent ion channels. Intracellular Ca2+, together with diacylglycerol, activates PKC, which has many protein targets, including ion channels. Thus, activation of the G-protein-dependent pathway affects cellular excitability though several different effectors. In parallel, G protein-independent pathways lead to activation of non-selective cationic currents and metabotropic synaptic currents and potentials. Here, we provide a survey of the membrane transport proteins responsible for these electrical effects of Group I metabotropic glutamate receptors.

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

Similar content being viewed by others

References

  • Abdul-Ghani MA, Valiante TA, Carlen PL, Pennefather PS (1996) Metabotropic glutamate receptors coupled to IP3 production mediate inhibition of IAHP in rat dentate granule neurons. J Neurophysiol 76:2691–2700

    Article  CAS  Google Scholar 

  • Ady V, Perroy J, Tricoire L et al (2014) Type 1 metabotropic glutamate receptors (mGlu1) trigger the gating of GluD2 delta glutamate receptors. EMBO Rep. https://doi.org/10.1002/embr.201337371

  • Alexander S, Mathie A, Peters JA (2011) Guide to receptors and channels (GRAC). Br J Pharmacol 164:S1–S324. https://doi.org/10.1111/j.1476-5381.2011.01649_1.x

  • Alexander SP, Davenport AP, Kelly E et al (2015) The concise guide to PHARMACOLOGY 2015/16: G protein-coupled receptors. Br J Pharmacol 172:5744–5869. https://doi.org/10.1111/bph.13348

  • Anwyl R (1999) Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev 29:83–120. https://doi.org/10.1016/S0165-0173(98)00050-2

  • Aramori I, Nakanishi S (1992) Signal transduction and pharmacological characteristics of a metabotropic glutamate receptor, mGluRl, in transfected CHO cells. Neuron 8:757–765. https://doi.org/10.1016/0896-6273(92)90096-V

  • Beqollari D, Kammermeier PJ (2010) Venus fly trap domain of mGluR1 functions as a dominant negative against group I mGluR signaling. J Neurophysiol 104:439–448. https://doi.org/10.1152/jn.00799.2009

  • Berg AP, Sen N, Bayliss DA (2007) TrpC3/C7 and Slo2.1 are molecular targets for Metabotropic glutamate receptor signaling in rat Striatal cholinergic Interneurons. J Neurosci 27:8845–8856. https://doi.org/10.1523/JNEUROSCI.0551-07.2007

  • Berridge MJ, Irvine RF (1984) Inositol trisphosphate, a novel second messenger in cellular signal transduction. Nature 312:315–321. https://doi.org/10.1038/312315a0

  • Bertaso F, Roussignol G, Worley P et al (2010) Homer1a-dependent crosstalk between NMDA and metabotropic glutamate receptors in mouse neurons. PLoS ONE 5:e9755. https://doi.org/10.1371/journal.pone.0009755

  • Biel M (2009) Cyclic Nucleotide-Regulated Cation Channels. In: Handbook of Cell Signaling. Elsevier, pp 9017–21. https://doi.org/10.1074/jbc.R800075200

  • Blaustein MP, Lederer WJ (1999) Sodium/calcium exchange: its physiological implications. Physiol Rev 79:763–854

    Article  CAS  Google Scholar 

  • Bond CT, Herson PS, Strassmaier T et al (2004) Small conductance Ca2+−activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J Neurosci 24:5301–5306. https://doi.org/10.1523/JNEUROSCI.0182-04.2004

  • Brager DH, Johnston D (2007) Plasticity of intrinsic excitability during long-term depression is mediated through mGluR-dependent changes in I(h) in hippocampal CA1 pyramidal neurons. J Neurosci 27:13926–13937. https://doi.org/10.1523/JNEUROSCI.3520-07.2007

  • Brodkin J, Bradbury M, Busse C et al (2002) Reduced stress-induced hyperthermia in mGluR5 knockout mice. Eur J Neurosci 16:2241–2244. https://doi.org/10.1046/j.1460-9568.2002.02294.x

  • Brown HF, DiFrancesco D, Noble SJ (1979) How does adrenaline accelerate the heart? Nature 280:235–236. https://doi.org/10.1038/280235a0

  • Carroll FY, Stolle A, Beart PM et al (2001) BAY36-7620: a potent non-competitive mGlu1 receptor antagonist with inverse agonist activity. Mol Pharmacol 59:965–973. https://doi.org/10.1124/mol.59.5.965

  • Cartmell J, Schoepp DD (2000) Regulation of neurotransmitter release by Metabotropic glutamate receptors. J Neurochem 75:889–907. https://doi.org/10.1046/j.1471-4159.2000.0750889.x

  • Cathala L, Paupardin-Tritsch D (1997) Neurotensin inhibition of the hyperpolarization-activated cation current (‘h) in the rat substantia nigra pars compacta implicates the protein kinase C pathway. J Physiol 503:87–97

    Article  CAS  Google Scholar 

  • Chen A, Hu WW, Jiang XL et al (2016) Molecular mechanisms of group I metabotropic glutamate receptor mediated LTP and LTD in basolateral amygdala in vitro. Psychopharmacology 234:681–694. https://doi.org/10.1007/s00213-016-4503-7

  • Chevaleyre V, Castillo PE (2004) Endocannabinoid-mediated metaplasticity in the hippocampus. Neuron. https://doi.org/10.1016/j.neuron.2004.08.036

  • Clark BP, Baker SR, Goldsworthy J et al (1997) (+)-2-methyl-4-Carboxyphenylglycine (LY367385) selectively Antagonises Metabotropic glutamate mGluR1 receptors. Bioorganic Med Chem Lett 7:2777–2780. https://doi.org/10.1016/S0960-894X(97)10071-3

  • Costantino G, Macchiarulo A, Pellicciari R (1999) Modeling of amino-terminal domains of group I metabotropic glutamate receptors: structural motifs affecting ligand selectivity. J Med Chem 42:5390–5401. https://doi.org/10.1021/jm990353c

  • Doherty AJ, Palmer MJ, Henley JM et al (1997) (RS)-2-Chloro-5-Hydroxyphenylglycine(CHPG) activates mGlu5, but not mGlu1, receptors expressed in CHO cells and potentiates NMDA responses in the hippocampus. Neuropharmacology 36:265–267. https://doi.org/10.1016/S0028-3908(97)00001-4

  • Doré AS, Okrasa K, Patel JC et al (2014) Structure of class C GPCR metabotropic glutamate receptor 5 transmembrane domain. Nature 511:557–562. https://doi.org/10.1038/nature13396

  • Doumazane E, Scholler P, Zwier JM et al (2011) A new approach to analyze cell surface protein complexes reveals specific heterodimeric metabotropic glutamate receptors. FASEB J 25:66–77. https://doi.org/10.1096/fj.10-163147

  • Edwards DA, Kim J, Alger BE (2006) Multiple mechanisms of Endocannabinoid response initiation in hippocampus. J Neurophysiol 95:67–75. https://doi.org/10.1152/jn.00813.2005

  • Ellaithy A, Younkin J, Gonzalez-Maeso J, Logothetis DE (2015) Positive Allosteric modulators of Metabotropic glutamate 2 receptors in schizophrenia treatment. Trends Neurosci 38:506–516. https://doi.org/10.1016/j.bbamem.2015.02.010.Cationic

  • Emery AC, DiRaddo JO, Miller E et al (2012) Ligand bias at Metabotropic glutamate 1a receptors: molecular determinants that distinguish β-Arrestin-mediated from G protein-mediated signaling. Mol Pharmacol 82:291–301. https://doi.org/10.1124/mol.112.078444

  • Enz R (2012) Structure of metabotropic glutamate receptor C-terminal domains in contact with interacting proteins. Front Mol Neurosci. https://doi.org/10.3389/fnmol.2012.00052

  • Faber ES (2009) Functions and modulation of neuronal SK channels. Cell Biochem Biophys 55:127–139. https://doi.org/10.1007/s12013-009-9062-7

  • Ferraguti F, Crepaldi L, Nicoletti F (2008) Metabotropic glutamate 1 receptor: current concepts and perspectives. Pharmacol Rev 60:536–81. https://doi.org/10.1124/pr.108.000166

  • Fiorillo CD, Williams JT (1998) Glutamate mediates an inhibitory postsynaptic potential in dopamine neurons. Nature 394:78–82. https://doi.org/10.1038/27919

  • Foord SM, Bonner TI, Neubig RR, et al (2005) International Union of Pharmacology. XLVI. G Protein-coupled receptor list. Pharmacol Rev 57: 279–288. https://doi.org/10.1124/pr.57.2.5

  • Galvez T, Parmentier ML, Joly C et al (1999) Mutagenesis and modeling of the GABAB receptor extracellular domain support a venus flytrap mechanism for ligand binding. J Biol Chem 274:13362–13369. https://doi.org/10.1074/jbc.274.19.13362

  • Gao F, Li F, Miao Y et al (2015) Group I metabotropic glutamate receptor agonist DHPG modulates Kir4.1 protein and mRNA in cultured rat retinal Müller cells. Neurosci Lett 588:12–17. https://doi.org/10.1016/j.neulet.2014.12.048

  • Gao Z-G, Jacobson KA (2016) On the selectivity of the Gαq inhibitor UBO-QIC: a comparison with the Gαi inhibitor pertussis toxin. Biochem Pharmacol 107:59–66. https://doi.org/10.1016/j.bcp.2016.03.003

  • Gao SH, Wen HZ, Shen LL, Zhao YD, Ruan HZ (2016) Activation of mGluR1 contributes to neuronal hyperexcitability in the rat anterior cingulate cortex via inhibition of HCN channels. Neuropharmacology 105:361–377. https://doi.org/10.1016/j.neuropharm.2016.01.036

  • Gasparini F, Lingenhohl K, Stoehr N et al (1999) 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 38:1493–1503. https://doi.org/10.1016/S0028-3908(99)00082-9

  • Gee CE, Benquet P, Gerber U (2003) Group I metabotropic glutamate receptors activate a calcium-sensitive transient receptor potential-like conductance in rat hippocampus. J Physiol 546:655–664. https://doi.org/10.1113/jphysiol.2002.032961

  • Gladding CM, Fitzjohn SM, Molnar E (2009) Metabotropic glutamate receptor-mediated long-term depression: molecular mechanisms. Pharmacol Rev. https://doi.org/10.1124/pr.109.001735

  • Glitsch MD (2009) Activation of native TRPC3 cation channels by phospholipase D. FASEB J 24:318–325. https://doi.org/10.1096/fj.09-134973

  • Grandes P, Mateos JM, Rüegg D et al (1994) Differential cellular localization of three splice variants of the mGluR1 metabotropic glutamate receptor in rat cerebellum. Neuroreport 5:2249–2252

    Article  CAS  Google Scholar 

  • Gregory KJ, Conn PJ (2015) Molecular insights into Metabotropic glutamate receptor Allosteric modulation s. Mol Pharmacol 88:188–202

    Article  CAS  Google Scholar 

  • Gueler N, Kukley M, Dietrich D (2007) TBOA-sensitive uptake limits glutamate penetration into brain slices to a few micrometers. Neurosci Lett 419:269–272. https://doi.org/10.1016/j.neulet.2007.04.035

  • Guérineau NC, Bossu JL, Gähwiler BH, Gerber U (1995) Activation of a nonselective cationic conductance by metabotropic glutamatergic and muscarinic agonists in CA3 pyramidal neurons of the rat hippocampus. J Neurosci 15(6):4395–4407

    Article  Google Scholar 

  • Hale CC, Bliler S, Quinn TP, Peletskaya EN (1997) Localization of an exchange inhibitory peptide (XIP) binding site on the cardiac sodium-calcium exchanger. Biochem Biophys Res Commun. https://doi.org/10.1006/bbrc.1997.6912

  • Hartmann J, Dragicevic E, Adelsberger H et al (2008) TRPC3 channels are required for synaptic transmission and motor coordination. Neuron. https://doi.org/10.1016/j.neuron.2008.06.009

  • Hartmann J, Karl RM, Alexander RPD et al (2014) STIM1 controls neuronal Ca2+ signaling, mGluR1-dependent synaptic transmission, and Cerebellar motor behavior. Neuron 82:635–644. https://doi.org/10.1016/j.neuron.2014.03.027

  • Hartmann J, Konnerth A (2015) TRPC3-dependent synaptic transmission in central mammalian neurons. J Mol Med. https://doi.org/10.1007/s00109-015-1298-7

  • Hathaway HA, Pshenichkin S, Grajkowska E et al (2015) Pharmacological characterization of mGlu1 receptors in cerebellar granule cells reveals biased agonism. Neuropharmacology. https://doi.org/10.1016/j.neuropharm.2015.02.007

  • Hayashi Y, Sekiyama N, Nakanishi S et al (1994) Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes. J Neurosci 14:3370–3377

    Article  CAS  Google Scholar 

  • Heuss C, Scanziani M, Gähwiler BH, Gerber U (1999) G-protein-independent signaling mediated by metabotropic glutamate receptors. Nat Neurosci 2:1070–1077. https://doi.org/10.1038/15996

  • Hibino H, Inanobe A, Furutani K et al (2010) Inwardly rectifying potassium channels: their structure, function, and physiological roles. Physiol Rev 90:291–366. https://doi.org/10.1152/physrev.00021.2009

  • Hille B, Dickson EJ, Kruse M et al (2014) Phosphoinositides regulate ion channels. Biochim Biophys Acta - Mol Cell Biol Lipids 1851:844–856. https://doi.org/10.1016/j.bbalip.2014.09.010

  • Hirono M, Konishi S, Yoshioka T (1998) Phospholipase C-independent group I Metabotropic glutamate receptor-mediated inward current in mouse Purkinje cells. Biochem Biophys Res Commun. https://doi.org/10.1006/bbrc.1998.9465

  • Hirono M, Yoshioka T, Konishi S (2001) GABAB receptor activation enhances mGluR-mediated responses at cerebellar excitatory synapses. Nature Neurosci 4:1207–1216. https://doi.org/10.1038/nn764

  • Holmes KH, Keele NB, Shinnick-Gallagher P (1996) Loss of mGluR-mediated hyperpolarizations and increase in mGluR depolarizations in basolateral amygdala neurons in kindling-induced epilepsy. J Neurophysiol 76(4):2808–2812

    Article  CAS  Google Scholar 

  • Holohean AM, Hackman JC, Davidoff RA (1999) Mechanisms involved in the metabotropic glutamate receptor-enhancement of NMDA-mediated motoneurone responses in frog spinal cord. Br J Pharmacol 126:333–341. https://doi.org/10.1038/sj.bjp.0702263

  • Horne AL, Simmonds MA (1989) The pharmacology of quisqualate and ampa in the cerebral cortex of the rat in vitro. Neuropharmacology 28:1113–1118. https://doi.org/10.1016/0028-3908(89)90125-1

  • Houamed KM, Kuijper JL, Gilbert TL et al (1991) Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain. Science 252:1318–1321

    Article  CAS  Google Scholar 

  • Hovelsø N, Sotty F, Montezinho LP et al (2012) Therapeutic potential of metabotropic glutamate receptor modulators. Curr Neuropharmacol 10:12–48. https://doi.org/10.2174/157015912799362805

  • Ito I, Kohda A, Tanabe S, Hirose E (1992) 3, 5-Dihydroxyphenylglycine: a potent agonist of metabotropic glutamate receptors. Neuroreport 3:1013–1016

    Article  CAS  Google Scholar 

  • Iwamoto T, Watano T, Shigekawa M (1996) A novel isothiourea derivative selectively inhibits the reverse mode of Na+/Ca2+ exchange in cells expressing NCX1. J Biol Chem 271:22391–22397. https://doi.org/10.1074/jbc.271.37.22391

  • Ji M, Miao Y, Dong L-D et al (2012) Group I mGluR-mediated inhibition of Kir channels contributes to retinal Müller cell gliosis in a rat chronic ocular hypertension model. J Neurosci 32:12744–12755. https://doi.org/10.1523/JNEUROSCI.1291-12.2012

  • Jian K, Cifelli P, Pignatelli A et al (2010) Metabotropic glutamate receptors 1 and 5 differentially regulate bulbar dopaminergic cell function. Brain Res 1354:47–63. https://doi.org/10.1016/j.brainres.2010.07.104

  • Jingami H, Nakanishi S, Morikawa K (2003) Structure of the metabotropic glutamate receptor. Curr Opin Neurobiol. https://doi.org/10.1016/S0959-4388(03)00067-9

  • Kammermeier PJ (2012) The orthosteric agonist 2-chloro-5-hydroxyphenylglycine activates mGluR5 and mGluR1 with similar efficacy and potency. BMC Pharmacol 12:6. https://doi.org/10.1186/1471-2210-12-6

  • Kano M, Watanabe T (2017) Open Peer Review Type-1 metabotropic glutamate receptor signaling in cerebellar Purkinje cells in health and disease [version 1; referees: 3 approved]. https://doi.org/10.12688/f1000research.10485.1

  • Kanumilli S, Toms NJ, Venkateswarlu K et al (2002) Functional coupling of rat metabotropic glutamate 1a receptors to phospholipase D in CHO cells: involvement of extracellular Ca2+, protein kinase C, tyrosine kinase and rho-a. Neuropharmacology. https://doi.org/10.1016/S0028-3908(01)00161-7

  • Karakossian MH, Otis TS (2004) Excitation of cerebellar interneurons by group I metabotropic glutamate receptors. J Neurophysiol 92:1558–1565. https://doi.org/10.1152/jn.00300.2004

  • Keele NB, Arvanov VL, Shinnick-Gallagher P (1997) Quisqualate-preferring metabotropic glutamate receptor activates Na-Ca2+ exchange in rat basolateral amygdala neurones. J Physiol 499:87–104. https://doi.org/10.1113/jphysiol.1997.sp021913

  • Keele NB, Zinebi F, Neugebauer V, Shinnick-Gallagher P (2000) Epileptogenesis up-regulates metabotropic glutamate receptor activation of sodium-calcium exchange current in the amygdala. J Neurophysiol 83:2458–2462

    Article  CAS  Google Scholar 

  • Keselman I, Fribourg M, Felsenfeld DP, Logothetis DE (2007) Mechanism of PLC-mediated Kir3 current inhibition. Channels 1:113–123. https://doi.org/10.4161/chan.4321

  • Kim SJ, Kim YS, Yuan JP et al (2003) Activation of the TRPC1 cation channel by metabotropic glutamate receptor mGluR1. Nature 426:285–291. https://doi.org/10.1038/nature02162

  • Kinney GG, Brien JAO, Lemaire W et al (2005) A novel selective positive Allosteric modulator of Metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther 313:199–206. https://doi.org/10.1124/jpet.104.079244.tive

  • Knoflach F, Mutel V, Jolidon S et al (2001) Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site. Proc Natl Acad Sci U S A 98:13402–13407. https://doi.org/10.1073/pnas.231358298

  • Kobrinsky E, Mirshahi T, Zhang H et al (2000) Receptor-mediated hydrolysis of plasma membrane messenger PIP2 leads to K+−current desensitization. Nat Cell Biol 2:507–514. https://doi.org/10.1038/35019544

  • Kramer PF, Williams JT (2016) Calcium release from stores inhibits GIRK. Cell Rep 17:3246–3255. https://doi.org/10.1016/j.celrep.2016.11.076

  • Kreibich TA, Chalasani SH, Raper JA (2004) The neurotransmitter glutamate reduces axonal responsiveness to multiple repellents through the activation of metabotropic glutamate receptor 1. J Neurosci 24:7085–7095. https://doi.org/10.1523/JNEUROSCI.0349-04.2004

  • Kreitzer AC, Regehr WG (2001) Retrograde inhibition of presynaptic calcium influx by endogenous cannabinoids at excitatory synapses onto Purkinje cells. Neuron 29:717–727. https://doi.org/10.1016/S0896-6273(01)00246-X

  • Krueger DD, Osterweil EK, Bear MF (2010) Activation of mGluR5 induces rapid and long-lasting protein Kinase D Phosphorylation in Hippocampal neurons. J Mol Neurosci 42:1–8. https://doi.org/10.1007/s12031-010-9338-9

  • Kubota H, Nagao S, Obata K, Hirono M (2014) mGluR1-mediated excitation of cerebellar GABAergic interneurons requires both G protein-dependent and Src-ERK1/2-dependent signaling pathways. PLoS ONE 9:e106316. https://doi.org/10.1371/journal.pone.0106316

  • Kunishima N, Shimada Y, Tsuji Y et al (2000) Structural basis of glutamate recognition by a dimeric metabotropic glutamate receptor. Nature 407:971–977. https://doi.org/10.1038/35039564

  • Kushmerick C (2004) Retroinhibition of Presynaptic Ca2+ currents by Endocannabinoids released via postsynaptic mGluR activation at a calyx synapse. J Neurosci. https://doi.org/10.1523/JNEUROSCI.0768-04.2004

  • Latorre R, Castillo K, Carrasquel-Ursulaez W, Sepulveda RV, Gonzalez-Nilo F, Gonzalez C, Alvarez O (2016) Molecular determinants of BK Channel functional diversity and functioning. Physiol Rev 97:39–87. https://doi.org/10.1152/physrev.00001.2016

  • Layton ME (2005) Subtype-selective noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1). Curr Top Med Chem 5:859–867. https://doi.org/10.2174/1568026054750245

  • Lea PM IV, Faden AI (2006) Metabotropic glutamate receptor subtype 5 antagonists MPEP and MTEP. CNS Drug Rev 12:149–166. https://doi.org/10.1111/j.1527-3458.2006.00149.x

  • Li Q, Cui P, Miao Y et al (2016) Activation of group I metabotropic glutamate receptors regulates the excitability of rat retinal ganglion cells by suppressing Kir and I h. Brain Struct Funct 222:813–830. https://doi.org/10.1007/s00429-016-1248-3

  • Li Z, Matsuoka S, Hryshko LV et al (1994) Cloning of the NCX2 isoform of the plasma membrane Na(+)-Ca2+ exchanger. J Biol Chem 269:17434–17439

    CAS  PubMed  Google Scholar 

  • Li Z, Nicoll DA, Collins A et al (1991) Identification of a peptide inhibitor of the cardiac sarcolemmal Na(+)-Ca2+ exchanger. J Biol Chem 266:1014–1020

    CAS  PubMed  Google Scholar 

  • Linn CL (2000) Second messenger pathways involved in up-regulation of an L-type calcium channel. Vis Neurosci 17:473–482. https://doi.org/10.1164/ajrccm.159.3.9607099

  • Litschig S, Gasparini F, Rueegg D et al (1999) CPCCOEt, a noncompetitive metabotropic glutamate receptor 1 antagonist, inhibits receptor signaling without affecting glutamate binding. Mol Pharmacol 55:453–461. https://doi.org/10.1164/ajrccm.159.3.9607099

  • Logothetis DE, Kurachi Y, Galper J et al (1987) The βγ subunits of GTP-binding proteins activate the muscarinic K+ channel in heart. Nature 325:321–326. https://doi.org/10.1038/325321a0

  • López-Bendito G, Shigemoto R, Fairén A, Luján R (2002) Differential distribution of group I metabotropic glutamate receptors during rat cortical development. Cereb Cortex 12:625–638

    Article  Google Scholar 

  • Ludwig A, Zong X, Jeglitsch M et al (1998) A family of hyperpolarization-activated mammalian cation channels. Nature 393:587–591. https://doi.org/10.1038/31255

  • Maejima T, Hashimoto K, Yoshida T et al (2001) Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron. https://doi.org/10.1016/S0896-6273(01)00375-0

  • Maksymetz J, Moran SP, Conn PJ (2017) Targeting metabotropic glutamate receptors for novel treatments of schizophrenia. Mol Brain 10:15. https://doi.org/10.1186/s13041-017-0293-z

  • Malherbe A, Kew JNC, Richards JG et al (2002) Identification and characterization of a novel splice variant of the metabotropic glutamate receptor 5 gene in human hippocampus and cerebellum. Mol Brain Res 109:168–178. https://doi.org/10.1016/S0169-328X(02)00557-0

  • Mary S, Gomeza J, Prézeau L et al (1998) A cluster of basic residues in the carboxyl-terminal tail of the short metabotropic glutamate receptor 1 variants impairs their coupling to phospholipase C. J Biol Chem. https://doi.org/10.1074/jbc.273.1.425

  • Masu M, Tanabe Y, Tsuchida K et al (1991) Sequence and expression of a metabotropic glutamate receptor. Nature. https://doi.org/10.1038/349760a0

  • Morishita W, Kirov SA, Alger BE (1998) Evidence for metabotropic glutamate receptor activation in the induction of depolarization-induced suppression of inhibition in hippocampal CA1. J Neurosci 18:4870–4882

    Article  CAS  Google Scholar 

  • Moroni F, Lombardi G, Thomsen C et al (1997) Pharmacological characterization of 1-aminoindan-1,5-dicarboxylic acid, a potent mGluR1 antagonist. J Pharmacol Exp Ther 281:721–729

    CAS  PubMed  Google Scholar 

  • Muto T, Tsuchiya D, Morikawa K, Jingami H (2007) Structures of the extracellular regions of the group II/III metabotropic glutamate receptors. Proc Natl Acad Sci U S A. https://doi.org/10.1073/pnas.0611577104

  • Nakanishi S (1992) Molecular diversity of glutamate receptors and implications for brain function. Science 258:597–603. https://doi.org/10.1126/science.1329206

  • Netzeband JG, Gruol DL (2008) mGluR1 agonists elicit a ca 2+ signal and membrane hyperpolarization mediated by apamin-sensitive potassium channels in immature rat purkinje neurons. J Neurosci Res 86:293–305. https://doi.org/10.1002/jnr.21493

  • Nicoletti F, Bockaert J, Collingridge GL et al (2011) Metabotropic glutamate receptors: from the workbench to the bedside. Neuropharmacology 60:1017–1041. https://doi.org/10.1016/j.neuropharm.2010.10.022

  • Nicoll DA, Longoni S, Philipson KD (1990) Molecular cloning and functional expression of the cardiac sarcolemmal Na(+)-Ca2+ exchanger. Science 250:562–565. https://doi.org/10.1126/science.1700476

  • Nicoll DA, Quednau BD, Qui Z et al (1996) Cloning of a third mammalian Na+−Ca2+ exchanger, NCX3. J Biol Chem 271:24914–24921. https://doi.org/10.1074/jbc.271.40.24914

  • Niswender CM, Conn PJ (2010) Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50:295–322. https://doi.org/10.1146/annurev.pharmtox.011008.145533.Metabotropic

  • Nugent FS, Niehaus JL, Kauer JA (2009) PKG and PKA signaling in LTP at GABAergic synapses. Neuropsychopharmacology 34:1829–1842. https://doi.org/10.1038/jid.2014.371

  • O’Hara PJ, Sheppard PO, Thorgersen H et al (1993) The ligand-binding domain in metabotropic glutamate receptors is related to bacterial periplasmatic binding proteins. Neuron 11:41–52. https://doi.org/10.1016/0896-6273(93)90269-W

  • Ohno-Shosaku T, Shosaku J, Tsubokawa H, Kano M (2002) Cooperative endocannabinoid production by neuronal depolarization and group I metabotropic glutamate receptor activation. Eur J Neurosci. https://doi.org/10.1046/j.1460-9568.2002.01929.x

  • Olmo IG, Ferreira-Vieira TH, Ribeiro FM (2016) Dissecting the signaling pathways involved in the crosstalk between Metabotropic glutamate 5 and Cannabinoid type 1 receptors. Mol Pharmacol. https://doi.org/10.1124/mol.116.104372

  • Pin J-P, De Colle C, Bessis A-S, Acher F (1999) New perspectives for the development of selective metabotropic glutamate receptor ligands. Eur J Pharmacol 375:277–294. https://doi.org/10.1016/0896-6273(93)90269-W

  • Pin J-P, Joly C, Heinemann SF, Bockaert J (1994) Domains involved in the specificity of G protein activation in phospholipase C-coupled metabotropic glutamate receptors. EMBO J 13:342–348

    Article  CAS  Google Scholar 

  • Rainnie DG, Holmes KH, Shinnick-Gallagher P (1994) Activation of postsynaptic Metabotropic glutamate receptors by trans-ACPD hyperpolarizes neurons of the Basolateral Amygdala. J Neurosci 14:7208–7220

    Article  CAS  Google Scholar 

  • Ribeiro FM, Vieira LB, Pires RGW et al (2017) Metabotropic glutamate receptors and neurodegenerative diseases. Pharmacol Res. https://doi.org/10.1016/j.phrs.2016.11.013

  • Romano C, Yang WL, O’Malley KL (1996) Metabotropic glutamate receptor 5 is a disulfide-linked dimer. J Biol Chem 271:28612–28616. https://doi.org/10.1074/jbc.271.45.28612

  • Rondard P, Pin JP (2015) Dynamics and modulation of metabotropic glutamate receptors. Curr Opin Pharmacol 20:95–106. https://doi.org/10.1016/j.coph.2014.12.001

  • Santo-Domingo J, Vay L, Hernández-SanMiguel E et al (2007) The plasma membrane Na + /ca 2+ exchange inhibitor KB-R7943 is also a potent inhibitor of the mitochondrial ca 2+ uniporter. Br J Pharmacol 151:647–654. https://doi.org/10.1038/sj.bjp.0707260

  • Santoro B, Liu DT, Yao H et al (1998) Identification of a gene encoding a Hyperpolarization-activated Pacemaker Channel of brain. Cell 93:717–729. https://doi.org/10.1016/S0092-8674(00)81434-8

  • Schoepp DD, Conn PJ (1993) Metabotropic glutamate receptors in brain function and pathology. Trends Pharmacol Sci 14:13–20. https://doi.org/10.1016/0165-6147(93)90107-U

  • Schoepp DD, Goldsworthy J, Johnson BG et al (1994) 3,5-dihydroxyphenylglycine is a highly selective agonist for phosphoinositide-linked metabotropic glutamate receptors in the rat hippocampus. J Neurochem 63:769–772. https://doi.org/10.1046/j.1471-4159.1994.63020769.x

  • Schoepp DD, Jane DE, Monn JA (1999) Pharmacological agents acting at subtypes of metabotropic glutamate receptors. Neuropharmacology 38:1431–1476. https://doi.org/10.1016/S0028-3908(99)00092-1

  • Schrage R, Schmitz A-L, Gaffal E et al (2015) The experimental power of FR900359 to study Gq-regulated biological processes. Nat Commun 6:10156. https://doi.org/10.1038/ncomms10156

  • Sekizawa S, Bonham AC (2006) Group I metabotropic glutamate receptors on second-order baroreceptor neurons are tonically activated and induce a Na+−Ca2+ exchange current. J Neurophysiol 95:882–892. https://doi.org/10.1152/jn.00772.2005

  • Sengmany K, Singh J, Stewart GD et al (2017) Biased allosteric agonism and modulation of metabotropic glutamate receptor 5: implications for optimizing preclinical neuroscience drug discovery. Neuropharmacology 115:60–72. https://doi.org/10.1016/j.neuropharm.2016.07.001

  • Shah MM (2014) Cortical HCN channels: function, trafficking and plasticity. J Physiol 592:2711–2719. https://doi.org/10.1113/jphysiol.2013.270058

  • Sharon D, Vorobiov D, Dascal N (1997) Positive and negative coupling of the Metabotropic glutamate receptors to a G protein–activated K + channel, GIRK, in Xenopus Oocytes. J Gen Physiol 109:477–490. https://doi.org/10.1085/jgp.109.4.477

  • Shen K-Z, Johnson SW (2013) Group I mGluRs evoke K-ATP current by intracellular Ca2+ mobilization in rat subthalamus neurons. J Pharmacol Exp Ther 345:139–150. https://doi.org/10.1124/jpet.112.201566

  • Shim HG, Jang S-S, Jang DC et al (2016) mGlu 1 receptor mediates homeostatic control of intrinsic excitability through I h in cerebellar Purkinje cells. J Neurophysiol 115:2446–2455. https://doi.org/10.1152/jn.00566.2015

  • Sladeczek F, Pin JP, Récasens M et al (1985) Glutamate stimulates inositol phosphate formation in striatal neurones. Nature 317:717–719

    Article  CAS  Google Scholar 

  • Suh B-C, Hille B (2008) PIP2 is a necessary cofactor for ion channel function: how and why? Annu Rev Biophys 37:175–195. https://doi.org/10.1146/annurev.biophys.37.032807.125859

  • Sugiyama H, Ito I, Hirono C (1987) A new type of glutamate receptor linked to inositol phospholipid metabolism. Nature 325:531–533. https://doi.org/10.1038/325531a0

  • Takahashi K, Tsuchida K, Tanabe Y et al (1993) Role of the large extracellular domain of metabotropic glutamate receptors in agonist selectivity determination. J Biol Chem 268:19341–19345

    CAS  PubMed  Google Scholar 

  • Tempia F, Miniaci MC, Anchisi D, Strata P (1998) Postsynaptic current mediated by metabotropic glutamate receptors in cerebellar Purkinje cells. J Neurophysiol 80:520–528

    Article  CAS  Google Scholar 

  • Topolnik L, Azzi M, Morin F et al (2006) mGluR1/5 subtype-specific calcium signalling and induction of long-term potentiation in rat hippocampal oriens/alveus interneurones. J Physiol 575:115–131. https://doi.org/10.1113/jphysiol.2006.112896

  • Tsuchiya D, Kunishima N, Kamiya N et al (2002) Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd3+. Proc Natl Acad Sci U S A 99:2660–2665. https://doi.org/10.1073/pnas.052708599

  • Uesaka N, Uchigashima M, Mikuni T et al (2015) Retrograde signaling for climbing fiber synapse elimination. Cerebellum 14:4–7. https://doi.org/10.1007/s12311-014-0615-y

  • Varma N, Carlson GC, Ledent C, Alger BE (2001) Metabotropic glutamate receptors drive the endocannabinoid system in hippocampus. J Neurosci 21:RC188

    Article  CAS  Google Scholar 

  • von Gersdorff H, Borst JGG (2002) Short-term plasticity at the calyx of held. Nat Rev Neurosci 3:53–64. https://doi.org/10.1038/nrn705

  • Williams AD, Jung S, Poolos NP (2015) Protein kinase C bidirectionally modulates I h and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression in hippocampal pyramidal neurons. J Physiol 59313:2779–279213. https://doi.org/10.1113/JP270453

  • Wisler JW, Xiao K, Thomsen AR, Lefkowitz RJ (2014) Recent developments in biased agonism. Curr Opin Cell Biol 27:18–24. https://doi.org/10.1016/j.ceb.2013.10.008

  • Wiśniewski K, Car H (2002) (S)-3,5-DHPG: a review. CNS Drug Rev 8:101–116

    Article  Google Scholar 

  • Wu L-J, Sweet T-B, Clapham DE (2010) International Union of Basic and Clinical Pharmacology. LXXVI. Current progress in the mammalian TRP Ion Channel family. Pharmacol Rev. https://doi.org/10.1124/pr.110.002725

  • Wu H, Wang C, Gregory KJ et al (2014) Structure of a class C GPCR metabotropic glutamate receptor 1 bound to an allosteric modulator. Science 344(80):58–64. https://doi.org/10.1126/science.1249489.Structure

  • Yoshida T, Hashimoto K, Zimmer A et al (2002) The cannabinoid CB1 receptor mediates retrograde signals for depolarization-induced suppression of inhibition in cerebellar Purkinje cells. J Neurosci 22:1690–1697

    Article  CAS  Google Scholar 

  • Zou J, Jiang J, Yang J (2017) Molecular basis for modulation of Metabotropic glutamate receptors and their drug actions by extracellular Ca2+. Int J Mol Sci 18:672. https://doi.org/10.3390/ijms18030672

Download references

Author information

Authors and Affiliations

  1. Graduate Program in Physiology and Pharmacology, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil

    Ana Maria Bernal Correa, Jennifer Diniz Soares Guimarães, Everton dos Santos e Alhadas & Christopher Kushmerick

  2. Departamento de Fisiologia e Biofísica – ICB, UFMG, Av. Pres. Antônio Carlos, 6627 – Pampulha, Belo Horizonte, MG, 31270-901, Brazil

    Christopher Kushmerick

Authors
  1. Ana Maria Bernal Correa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jennifer Diniz Soares Guimarães
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Everton dos Santos e Alhadas
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christopher Kushmerick
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christopher Kushmerick.

Ethics declarations

Conflict of interest

Ana Maria Bernal Correa declares that she has no conflicts of interest. Jennifer Diniz Soares Guimarães declares that she has no conflicts of interest. Everton dos Santos e Alhadas declares that he has no conflicts of interest. Christopher Kushmerick declares that he has no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

Additional information

This article is part of a Special Issue on ‘Latin America’ edited by Pietro Ciancaglini and Rosangela Itri.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Correa, A.M.B., Guimarães, J.D.S., dos Santos e Alhadas, E. et al. Control of neuronal excitability by Group I metabotropic glutamate receptors. Biophys Rev 9, 835–845 (2017). https://doi.org/10.1007/s12551-017-0301-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12551-017-0301-7

Keywords

Search

Navigation