Affinage

GRM6

Metabotropic glutamate receptor 6 · UniProt O15303

Length
877 aa
Mass
95.5 kDa
Annotated
2026-06-10
73 papers in source corpus 35 papers cited in narrative 35 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

GRM6 encodes mGluR6 (mGlu6), a class C metabotropic glutamate receptor expressed selectively in the inner nuclear layer of the retina, where it mediates synaptic transmission from photoreceptors to ON bipolar cells (PMID:8389366, PMID:7889569, PMID:9096137). Genetic ablation in mice selectively abolishes the ON visual response (loss of the ERG b-wave ON component) while leaving OFF pathways and retinal architecture intact, defining mGluR6 as the obligatory detector of glutamate at the ON bipolar dendrite (PMID:7889569). The receptor is enriched at dendritic tips of rod and cone ON bipolar cells, positioned at the base of the postsynaptic invagination, and shows highest agonist potency for L-AP4 and L-serine-O-phosphate (PMID:8389366, PMID:9279006, PMID:10870081). Signaling proceeds through Gαo rather than a cGMP/PDE cascade: mGluR6 couples preferentially to Gαoa/Gαob, and activated Gαo suppresses the constitutively active TRPM1-L cation channel, the downstream effector whose loss likewise eliminates ON photoresponses (PMID:10191311, PMID:17266783, PMID:19966281). mGluR6 nucleates and organizes a postsynaptic macromolecular complex, recruiting Gβ5-bound RGS7 and RGS11 GTPase-accelerating complexes — the RGS11·Gβ5·R9AP heterotrimer being anchored through mGluR6 — that accelerate Gαo deactivation, and is required for the dendritic-tip localization of TRPM1, Cacna1s, and these regulatory proteins (PMID:18001285, PMID:19625520, PMID:20007977, PMID:19966281, PMID:21832182, PMID:24519419). The transduction channel is subject to Ca²⁺-dependent feedback through calcineurin, producing use-dependent desensitization (PMID:10844016, PMID:12205131, PMID:15146044). mGluR6 acquires complex N-glycosylation in the Golgi that is required for surface trafficking, synaptic localization, G-protein coupling, and trans-synaptic binding to presynaptic ELFN1/ELFN2 adhesion proteins; ELFN1 binds via its LRR/LRRCT region and mGluR6 reciprocally enriches ELFN1 presynaptically (PMID:34793838, PMID:38428819, PMID:40930976, PMID:42201444). CryoEM of agonist-bound mGlu6 reveals an asymmetric homodimer pre-organized for Gαo coupling through a noncanonical cysteine-rich domain/ECL2 interface (PMID:41803130). Multiple CSNB-associated missense mutations cause disease through loss of Gαo coupling, Golgi-bypass trafficking defects, or impaired ELFN1 binding and synaptic mislocalization (PMID:19666700, PMID:39681475, PMID:41803130).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Establishing that mGluR6 is a glutamate receptor coupled to inhibitory G proteins with a retina-restricted expression pattern defined its molecular identity and tissue context.

    Evidence cDNA cloning and CHO cell cAMP assay with pharmacology, plus in situ hybridization

    PMID:8389366

    Open questions at the time
    • Did not identify the in vivo effector channel
    • Coupling shown only in heterologous cells, not native bipolar cells
  2. 1995 High

    Knockout established that mGluR6 is required specifically for ON-pathway synaptic transmission, separating its role from OFF signaling and retinal development.

    Evidence Gene-targeted mouse, electroretinography, histology

    PMID:7889569

    Open questions at the time
    • Did not define the signaling cascade downstream of the receptor
    • Effector channel unidentified
  3. 1997 High

    Promoter-reporter transgenics and ultrastructural immunolabeling localized mGluR6 to dendritic tips of both rod and cone ON bipolar cells, fixing its precise synaptic site.

    Evidence Promoter-lacZ transgenic mice and immunoelectron microscopy in rat retina

    PMID:9096137 PMID:9279006 PMID:9357538

    Open questions at the time
    • Did not resolve which G protein operates in native cells
    • Exact distance from release site refined only later
  4. 1999 High

    Direct electrophysiology in ON bipolar cells showed signaling proceeds via Gαo and not a cGMP/PDE cascade, resolving the native transduction mechanism.

    Evidence Whole-cell patch-clamp with intracellular dialysis of G-protein subunits, cGMP analogs, and antibodies in salamander retinal slices

    PMID:10191311

    Open questions at the time
    • Effector cation channel not yet molecularly identified
    • Gα subtype specificity quantified only later
  5. 2002 High

    Ca²⁺ entry through the transduction channel was shown to drive feedback closure via calcineurin, defining the basis of use-dependent desensitization.

    Evidence Whole-cell recordings with Ca²⁺ chelators, calcineurin inhibitors, and active/inactive calcineurin constructs in salamander slices

    PMID:10844016 PMID:12205131 PMID:15146044

    Open questions at the time
    • Molecular target of calcineurin dephosphorylation not identified
    • Effector channel identity still unknown at the time
  6. 2007 High

    G-protein reconstitution plus single-cell RT-PCR established Gαo as the predominant native coupling partner, refining the cascade's first step.

    Evidence PTX-insensitive Gα reconstitution in sympathetic neurons and single-cell RT-PCR of ON bipolar cells

    PMID:17266783

    Open questions at the time
    • Did not address regulatory GAP machinery
    • Effector channel still unidentified
  7. 2009 High

    Identification of RGS7/RGS11·Gβ5·R9AP complexes anchored to mGluR6, and of TRPM1-L as the Gαo-regulated effector, completed the core architecture of the transduction cascade.

    Evidence Co-IP, immunofluorescence in null mice, in vitro GTPase reconstitution, and TRPM1 knockout phenotyping

    PMID:18001285 PMID:19625520 PMID:19666700 PMID:19966281 PMID:20007977

    Open questions at the time
    • RGS11 deletion alone had little kinetic effect, leaving redundancy unresolved
    • Mechanism of mGluR6-TRPM1 functional coupling not fully defined
  8. 2011 High

    mGluR6 was shown to be required to target and maintain TRPM1 (and a nyctalopin-containing complex) at dendritic tips, establishing the receptor as an organizer of the postsynaptic signaling apparatus.

    Evidence Nyctalopin proteomics, Co-IP, and immunofluorescence/electrophysiology in mGluR6-null mice

    PMID:21832182 PMID:22131384

    Open questions at the time
    • Direct mGluR6-TRPM1 binding interface not mapped
    • Whether mGluR6 acts on trafficking or stabilization left open
  9. 2014 High

    GPR179 and cascade-component knockouts revealed an interdependent macromolecular complex in which mGluR6 organizes localization of RGS proteins and Cacna1s and gates TRPM1 sensitivity.

    Evidence ERG, electrophysiology, and immunofluorescence across multiple knockout mouse lines

    PMID:24519419 PMID:24790204

    Open questions at the time
    • Direct binding partners within the complex not all biochemically defined
    • Stoichiometry of the complex unknown
  10. 2016 Medium

    Systematic cascade knockouts showed Gαo1 supports downstream component expression and that the postsynaptic complex exerts retrograde effects on presynaptic matrix proteins, extending mGluR6's role to trans-synaptic organization.

    Evidence Immunofluorescence quantification in Gαo1, mGluR6, and Gβ3 knockout mice

    PMID:27037829

    Open questions at the time
    • No direct binding assay for the retrograde link
    • Molecular mediator of the trans-synaptic effect unidentified
  11. 2024 High

    Complex Golgi N-glycosylation was shown to be required for surface trafficking, synaptic localization, G-protein coupling, and ELFN1/ELFN2 binding, linking receptor maturation to synaptic adhesion.

    Evidence Glycosidase assays, site-directed N-to-Q mutagenesis, ELFN pulldowns, and AAV rescue in mGluR6-null bipolar cells

    PMID:33067823 PMID:37352898 PMID:38428819 PMID:39681475 PMID:42201444

    Open questions at the time
    • Individual site contributions partially divergent across studies
    • ER retention and Golgi sorting determinants only mapped in heterologous cells
  12. 2025 High

    ELFN1 binding was localized to its LRR/LRRCT domain, and mGluR6 and ELFN1 were shown to mutually enrich each other across the synapse, defining a bidirectional trans-synaptic adhesion mechanism.

    Evidence In vitro ELFN1 domain-deletion binding plus AAV rescue in mGluR6-null mice

    PMID:34793838 PMID:40930976 PMID:41448371

    Open questions at the time
    • Functional consequence of ELFN1 enrichment for transmission not fully resolved
    • Upper-lobe Golgi sorting determinant defined only in heterologous cells
  13. 2026 High

    CryoEM of agonist-bound mGlu6 revealed an asymmetric dimer pre-organized for Gαo coupling through a noncanonical CRD/ECL2 interface and classified diverse mechanistic consequences of CSNB mutations.

    Evidence CryoEM structure determination with interface mutagenesis and functional Gαo/surface-trafficking assays

    PMID:41803130

    Open questions at the time
    • No structure with bound G protein or effector complex
    • Structural basis of TRPM1 regulation not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How Gαo molecularly couples to and suppresses TRPM1, and the structural arrangement of the full mGluR6-Gαo-RGS-TRPM1 signaling complex, remain unresolved.
  • No direct structural or biochemical model of the mGluR6-TRPM1 functional link
  • Mechanism by which calcineurin gates the channel target unidentified
  • In vivo stoichiometry of the postsynaptic complex unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0060089 molecular transducer activity 3 GO:0098631 cell adhesion mediator activity 3
Localization
GO:0005794 Golgi apparatus 3 GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-112316 Neuronal System 2 R-HSA-9709957 Sensory Perception 2
Partners
ELFN1ELFN2GNAO1GNB5GPR179RGS11RGS7TRPM1
Complex memberships
RGS11·Gβ5·R9APRGS7·Gβ5mGluR6-TRPM1-nyctalopin postsynaptic complex

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1993 mGluR6 (871 aa) inhibits forskolin-stimulated cAMP accumulation when expressed in CHO cells, demonstrating coupling to Gi/o-type G proteins. It shows highest agonist selectivity for L-AP4 and L-serine-O-phosphate (one order of magnitude more potent than L-glutamate), and its mRNA is restricted to the inner nuclear layer of the retina where ON-bipolar cells reside. cDNA cloning, CHO cell transfection with cAMP assay, northern blot and in situ hybridization The Journal of biological chemistry High 8389366
1995 Genetic knockout of mGluR6 in mice abolishes ON visual responses (loss of ERG b-wave ON component) while OFF responses remain intact, demonstrating mGluR6 is essential for synaptic transmission from photoreceptors to ON bipolar cells. Retinal cell organization and optic fiber projections were unchanged. Gene targeting (knockout mouse), electroretinography, histology, optokinetic behavior Cell High 7889569
1997 The 9.5 kb 5' upstream sequence of the mGluR6 gene drives cell-specific expression in rod bipolar cells (PKC-positive) and ON-type cone bipolar cells in transgenic mice, matching the endogenous temporal and spatial expression pattern during retinal development. Transgenic mice with mGluR6 promoter driving lacZ reporter, X-gal staining, immunostaining, developmental ontogeny analysis The Journal of neuroscience High 9096137
1997 mGluR6 is expressed in the dendritic tips of ON cone bipolar cells (not only rod bipolar cells) in rat retina, as shown by ultrastructural immunostaining of serial sections; approximately half of dendritic tips contacting cones stain for mGluR6. Immunoelectron microscopy with serial ultrathin sections of rat retina Visual neuroscience High 9279006
1997 (S)-Homo-AMPA is a specific agonist at mGlu6 (EC50 = 58 µM, comparable to glutamate EC50 = 20 µM) with no significant activity at mGlu1-5 or mGlu7 or ionotropic glutamate receptors; (R)-Homo-AMPA is inactive at mGlu1-7. Functional pharmacology assay in heterologous expression system, chiral resolution and configurational assignment by NMR and CD Journal of medicinal chemistry High 9357538
1997 Human mGluR6 cloned from retinal cDNA library inhibits adenylate cyclase via a pertussis toxin-sensitive G-protein when stably expressed in CHO cells. Agonist rank order: L-AP4 > L-serine-O-phosphate > L-glutamate > quisqualate = (1S,3R)-ACPD. mRNA is detected only in the inner nuclear layer of human retina, not in human brain. Stable CHO cell expression, cAMP assay, pertussis toxin treatment, in situ hybridization, PCR Neuropharmacology High 9144651
1999 mGluR6 signals through Gαo rather than through phosphodiesterase/cGMP in ON bipolar cells. Dialysis with Gαo suppressed the cation current and occluded the glutamate response; Gαi or transducin Gβγ had no effect. Non-hydrolyzable cGMP analogs or PDE inhibitor IBMX did not block mGluR6 signaling. Anti-Gαo antibody reduced the glutamate response. Whole-cell patch-clamp recordings from ON bipolar cells in salamander retinal slices; intracellular dialysis with G-protein subunits, cGMP analogs, PDE inhibitors, and antibodies The Journal of neuroscience High 10191311
2000 mGluR6 is localized postsynaptically in the outer plexiform layer at the central element of the postsynaptic triad in all ON bipolar cell types (rod and cone) in monkey, cat, and rabbit retina. Ultrastructurally, mGluR6 resides ~400–800 nm from the vesicle release site, at the base of the invagination, not at the tip near the release zone. Confocal and electron microscopy with mGluR6 antibody directed to the human C-terminus; co-staining with S-opsin and cholecystokinin precursor markers The Journal of comparative neurology High 10870081
2000 Ca2+ influx through the mGluR6-gated cation channel provides feedback to close that channel, producing use-dependent run-down of glutamate-evoked currents in ON bipolar cells. This run-down is voltage-dependent and is prevented by intracellular BAPTA or by removing external Ca2+, establishing Ca2+-dependent regulation of the transduction channel downstream of mGluR6. Whole-cell recordings in salamander retinal slices; BAPTA chelation, Ca2+-free bath, voltage-clamp protocols The Journal of neuroscience High 10844016
2001 A splice variant of mGlu6 (mGlu6b) in rat retina contains an additional 88-nt exon with an in-frame stop codon, encoding a 508-aa truncated protein that retains the extracellular ligand-binding domain but lacks the transmembrane and intracellular domains, potentially functioning as a soluble glutamate receptor. RT-PCR, sequence analysis of rat retina cDNA, in situ hybridization Neuroreport Medium 11522953
2002 Ca2+-mediated depression of the mGluR6 transduction current in ON bipolar cells requires activation of calcineurin (a Ca2+/calmodulin-regulated phosphatase). Calcineurin inhibitors prevented depression; a constitutively active calcineurin (CaN420) restored depression even under BAPTA; calcineurin acts by reducing cation channel current, not by preventing mGluR6-mediated channel closure. Whole-cell recordings from ON bipolar cells in salamander retinal slices; pharmacological inhibitors, dialysis with active/inactive calcineurin constructs Journal of neurophysiology High 12205131
2004 Desensitization of the mGluR6 transduction current in ON bipolar cells is Ca2+-dependent: Ca2+ entry through the transduction channel triggers closure of that channel on a ~1 s timescale. BAPTA completely eliminated desensitization; EGTA reduced it; removing external Ca2+ prevented it, identifying Ca2+ entry through the channel as the trigger. Whole-cell recordings in salamander retinal slices; agonist/antagonist protocol, voltage-jump to vary Ca2+ influx, Ca2+ chelators The Journal of physiology High 15146044
2006 mGluR6 couples most efficiently to Gαoa and Gαob, moderately to Gαi1, and not at all to Gαz, rod transducin (GαTr-R), or cone transducin (GαTr-C) in a G-protein reconstitution assay. Single-cell RT-PCR of rat ON bipolar cells confirmed that Gαo is the predominant (essentially only) coupling partner expressed in these cells. PTX-insensitive Gα reconstitution in sympathetic neurons (SCG); single-cell RT-PCR of ON bipolar cells Visual neuroscience High 17266783
2007 Gbeta5-RGS7 and Gbeta5-RGS11 complexes co-localize with mGluR6 at the dendritic tips of ON bipolar cells. In mGluR6-null mice, RGS11, RGS7, and Gbeta5 shift away from the dendritic tips, demonstrating that mGluR6 is required for proper localization of these Gαo-regulatory complexes. Immunofluorescence, co-immunoprecipitation, dissociated bipolar cell preparation from mGluR6-null mice The European journal of neuroscience High 18001285
2008 N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide (PHCCC), an allosteric modulator of mGlu4, acts as a direct agonist at mGlu6 without allosteric modulatory properties, distinguishing mGlu6 pharmacology from mGlu4. Native calcium current modulation assay in isolated sympathetic neurons expressing mGlu4 or mGlu6; glutamate concentration-response curves with and without PHCCC European journal of pharmacology Medium 18593581
2008 Cacna1s (L-type VDCCα1 subunit) is localized postsynaptically at ON bipolar cell dendritic tips where it co-localizes with mGluR6. In Bassoon and Cacna1f mutant mice with reduced photoreceptor-to-bipolar cell signaling, Cacna1s labeling and mGluR6 labeling are severely downregulated, suggesting interdependence of postsynaptic protein expression. Immunocytochemistry with antibodies against Cacna1f, panalpha1, Cacna1s, mGluR6 in wild-type and mutant mouse retinas Investigative ophthalmology & visual science Medium 18952919
2009 mGluR6 signaling requires Gαo coupling. The E775K (human E781K) point mutation causes loss of Gαo coupling while retaining Gαi coupling, representing a switch in G-protein coupling that likely explains CSNB1 disease phenotype. Four other CSNB-linked point mutants showed trafficking impairment. G-protein coupling assay in heterologous expression system (SCG neurons); trafficking assay Molecular pharmacology Medium 19666700
2009 RGS11 forms an obligate trimeric complex with Gβ5 (short isoform) and R9AP (RGS9 anchor protein). This heterotrimer localizes to dendritic tips of ON bipolar cells through direct association with mGluR6. Both R9AP and mGluR6 contribute to proteolytic stabilization of the complex. Genetic elimination of RGS11 had little effect on Gαo deactivation kinetics in rod ON bipolar cells. Co-immunoprecipitation, immunofluorescence, electrophysiology (light response recordings) in mouse rod ON bipolar cells The Journal of neuroscience High 19625520
2009 R9AP potentiates the GTPase-accelerating protein (GAP) activity of RGS11·Gβ5 complex at Gαo by membrane co-localization and allosteric stimulation. Reconstitution of mGluR6-Gαo signaling in Xenopus oocytes showed that RGS11·Gβ5-mediated GTPase acceleration requires R9AP co-expression. Single-turnover GTPase assay (in vitro reconstitution), Xenopus oocyte reconstitution of mGluR6-Gαo signaling The Journal of biological chemistry High 20007977
2009 TRPM1 long form (TRPM1-L) is a constitutively active nonselective cation channel that localizes to the dendritic tips of ON bipolar cells co-localizing with mGluR6. TRPM1 null mice completely lose ON bipolar cell photoresponses. Gαo negatively regulates TRPM1-L activity downstream of mGluR6, establishing TRPM1-L as the effector channel in the mGluR6 cascade. Immunofluorescence, electrophysiology, TRPM1 null mouse phenotyping, heterologous expression of TRPM1-L with Gαo Proceedings of the National Academy of Sciences High 19966281
2011 Nyctalopin interacts with both TRPM1 and mGluR6 in a macromolecular complex at ON bipolar cell dendritic tips (identified by proteomic search). Disruption of mGluR6 prevents targeting of TRPM1 to the postsynaptic compartment of ON bipolar neurons, revealing that mGluR6 is required for postsynaptic TRPM1 localization. Proteomic search for nyctalopin-associated proteins, Co-immunoprecipitation, immunofluorescence in mGluR6 knockout mice The Journal of neuroscience High 21832182
2011 In mGluR6-null rod bipolar cells, TRPM1 channels are inactive rather than constitutively open. TRPM1 immunostaining at dendritic tips is greatly reduced (though some TRPM1 remains at soma/primary dendrites). Capsaicin-activated TRPM1 currents are absent in mGluR6-null cells. Gαo, Gβ3, and Gγ13 expression/distribution are unchanged in null mice. Electrophysiology (whole-cell patch-clamp), capsaicin application, immunofluorescence in mGluR6 knockout mouse retina Journal of neurophysiology High 22131384
2014 GPR179 controls the sensitivity of the mGluR6 cascade to gate TRPM1. Loss of GPR179 prevents localization of RGS7 and RGS11 to dendritic tips and directly impairs TRPM1 channel gating (capsaicin-evoked TRPM1 currents are severely compromised in Gpr179-null but not in RGS7/RGS11 double-KO rod BCs), suggesting GPR179 directly interacts with TRPM1. ERG, electrophysiology (noise analysis, standing current analysis, capsaicin gating), immunofluorescence in multiple knockout mouse lines The Journal of neuroscience High 24790204
2014 Cacna1s localization at ON bipolar cell dendritic tips depends on mGluR6 and other cascade components (Gαo1, Gβ3, Gγ13, TRPM1). Immunostaining for Cacna1s is severely reduced in mice lacking any of these components. mGluR6 expression developmentally precedes that of Cacna1s and RGS11, consistent with mGluR6 organizing the macromolecular complex. Immunohistochemistry in multiple knockout mouse retinas; RT-PCR for ON bipolar cell expression; Western blotting; developmental time-course Investigative ophthalmology & visual science Medium 24519419
2016 Deletion of Gαo1 in mice greatly reduced expression of downstream cascade components (Gβ3, Gγ13, Gβ5, RGS11, RGS7, R9AP) at dendritic tips, but did not affect mGluR6 or TRPM1 levels. Loss of mGluR6, Gαo1, or Gβ3 each reduced staining of matrix-associated proteins (pikachurin, dystroglycan, dystrophin) presynaptically, suggesting retrograde trans-synaptic effects mediated through the mGluR6 macromolecular complex. Immunofluorescence quantification in knockout mice lacking Gαo1, mGluR6, or Gβ3 The European journal of neuroscience Medium 27037829
2020 The mGluR6 C-terminal domain (CTD) contains ER retention motifs (cluster of basic amino acids). Deletion of residues 857–871 impairs surface localization and glutamate-induced G-protein responses, while deletion of 851–871 restores them; deletion of the entire CTD again impairs them. A surface-deficient mGluR6 mutant dominantly reduces surface levels of co-expressed surface-expressible mGluR6 via heteromeric complexes. Immunocytochemistry, surface biotinylation assay, electrophysiology in 293T cells and primary hippocampal neurons Journal of neurochemistry Medium 33067823
2021 Multiple regions in the mGluR6 ligand-binding domain are necessary for both synaptic localization in ON bipolar cells and ELFN1 binding in vitro, but not for plasma membrane localization in heterologous cells, indicating that synaptic targeting and secretory trafficking are controlled by different mechanisms. The mGluR6 C-terminus is dispensable for synaptic localization but is required for efficient TRPM1 trafficking to dendritic tips—a C-terminal deletion mutant has significantly reduced ability to rescue TRPM1 localization in mGluR6-null mice. Mutagenesis of mGluR6 ligand-binding domain and C-terminus, AAV rescue in mGluR6 null mice, immunofluorescence, in vitro ELFN1 binding pulldown The Journal of biological chemistry High 34793838
2023 Basic residues in the mGluR6 C-terminal domain serve as ER retention signals. alanine substitutions at these basic residues rescue surface expression of otherwise surface-deficient CTD-deletion mutants. Surface-deficient mGluR6 forms heteromeric complexes with full-length mGluR6 but is not rescued to the surface by co-expression, and it reduces the surface levels of surface-expressible co-expressed mGluR6. Immunocytochemistry, immunoprecipitation, flow cytometry of 293T cells expressing CTD mutants Molecular and cellular neurosciences Medium 37352898
2024 mGluR6 undergoes complex N-glycosylation acquired in the Golgi (demonstrated by PNGase F and Endo H treatment). ELFN1 and ELFN2 interact exclusively with the complex (Golgi-processed) glycosylated form of mGluR6. All four predicted N-glycosylation sites (N290, N445, N473, N561) are occupied. Mutation at N445 severely impairs ELFN1 and ELFN2 binding. Triple N-glycosylation mutants have little or no surface expression, but the quadruple mutant is completely mislocalized from dendritic tips in rod bipolar cells. Glycosidase treatment (PNGase F, Endo H), ELFN1/ELFN2 pulldown assays, single and multiple N-to-Q mutants in heterologous cells and rod bipolar cells (AAV delivery to mGluR6-null mice) The Journal of biological chemistry High 38428819
2024 Multiple CSNB-associated missense mutations in the mGluR6 extracellular ligand-binding domain cause a Golgi bypass trafficking defect: the mutant proteins acquire only core N-glycosylation (not complex Golgi-processed glycosylation) yet still reach the plasma membrane, and they fail to bind ELFN1. These mutants are mislocalized away from dendritic tips in bipolar cells, explaining loss of synaptic function. Glycosidase sensitivity assays (PNGase F/Endo H), ELFN1 binding pulldown, immunofluorescence in rod bipolar cells Life science alliance High 39681475
2025 The leucine-rich repeat (LRR) and LRRCT regions of the ELFN1 extracellular domain are necessary and sufficient for binding to mGluR6 (and other Group III mGluRs). In mGluR6-null mice, presynaptic ELFN1 in rod spherules loses its synaptic co-localization, and this is rescued by re-expressing mGluR6 in ON bipolar cells, demonstrating bidirectional mutual regulation of mGluR6 postsynaptic enrichment and ELFN1 presynaptic enrichment. In vitro binding experiments with ELFN1 domain deletions, immunofluorescence in mGluR6-null mice, AAV-mediated rescue with mGluR6-EGFP in ON bipolar cells, ELFN1-flag expression in rod photoreceptors The Journal of neuroscience High 40930976
2025 The upper lobe of the mGluR6 ligand-binding domain regulates secretory trafficking: small deletions in this region redirect mGluR6 to unconventional secretion with plasma membrane insertion of core-glycosylated (immature) protein, while larger deletions partially restore Golgi trafficking. This implicates an intraluminal interaction in the upper lobe as a Golgi sorting determinant. Glycosidase sensitivity assay (Endo H/PNGase F), surface biotinylation, immunofluorescence for ER/Golgi markers in heterologous cells expressing deletion mutants Molecular and cellular neurosciences Medium 41448371
2026 CryoEM structure of agonist-bound mGlu6 reveals an asymmetric homodimer in the absence of a G protein, demonstrating that agonist binding alone induces the homodimeric receptor asymmetry and pre-organizes the transmembrane domain dimer interface for G protein binding. A noncanonical interface between the cysteine-rich domain and extracellular loop 2 stabilizes the activation state; mutations in this interface impair rapid Gαo activation and surface targeting. Structural analysis of CSNB mutations reveals diverse effects: impaired surface trafficking, altered Gαo coupling, changed activation dynamics, and unexpected gain-of-function in some mutants. CryoEM structure determination, mutagenesis of cysteine-rich domain/ECL2 interface, functional assays for Gαo activation and surface trafficking Nature communications High 41803130
2026 N-glycosylation at four sites (N290, N445, N473, N561) in the mGluR6 extracellular domain is required for efficient G-protein coupling, cell surface transport (N290 and N445 mutations reduce surface levels), and interactions with synaptic adhesion molecules: N445Q impairs mGluR6-ELFN1 interaction; N473Q and N561Q facilitate it; mGluR6 co-immunoprecipitates with Lrit1 in co-transfected cells, and this interaction is promoted by N290Q and suppressed by N561Q. N-to-Q mutagenesis of individual and combined N-glycosylation sites, surface expression by flow cytometry, glutamate-induced G-protein-mediated response assay, pulldown with ELFN1, co-immunoprecipitation with LRIT1 in 293T cells Journal of molecular neuroscience Medium 42201444
1998 Light-induced CREB phosphorylation (PCREB) and c-fos gene expression in rod bipolar cells are lost in mGluR6-deficient mice, demonstrating that mGluR6 is required for light-stimulated transcriptional activation of CREB in these cells. Immunostaining for PCREB and c-fos in mGluR6 knockout mouse retina compared to wild-type; co-labeling with PKCα (rod bipolar marker) Brain research. Molecular brain research Medium 9675422

Source papers

Stage 0 corpus · 73 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
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 604 8389366
1995 Specific deficit of the ON response in visual transmission by targeted disruption of the mGluR6 gene. Cell 414 7889569
2009 TRPM1 is a component of the retinal ON bipolar cell transduction channel in the mGluR6 cascade. Proceedings of the National Academy of Sciences of the United States of America 248 19966281
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 203 15781871
2000 Localization of mGluR6 to dendrites of ON bipolar cells in primate retina. The Journal of comparative neurology 163 10870081
2015 Restoring the ON Switch in Blind Retinas: Opto-mGluR6, a Next-Generation, Cell-Tailored Optogenetic Tool. PLoS biology 162 25950461
2005 Mutations in GRM6 cause autosomal recessive congenital stationary night blindness with a distinctive scotopic 15-Hz flicker electroretinogram. Investigative ophthalmology & visual science 129 16249515
1999 The metabotropic receptor mGluR6 may signal through G(o), but not phosphodiesterase, in retinal bipolar cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 122 10191311
1997 ON cone bipolar cells in rat express the metabotropic receptor mGluR6. Visual neuroscience 112 9279006
2010 TRPM1: the endpoint of the mGluR6 signal transduction cascade in retinal ON-bipolar cells. BioEssays : news and reviews in molecular, cellular and developmental biology 93 20544736
2008 Effects of presynaptic mutations on a postsynaptic Cacna1s calcium channel colocalized with mGluR6 at mouse photoreceptor ribbon synapses. Investigative ophthalmology & visual science 92 18952919
2011 TRPM1 forms complexes with nyctalopin in vivo and accumulates in postsynaptic compartment of ON-bipolar neurons in mGluR6-dependent manner. The Journal of neuroscience : the official journal of the Society for Neuroscience 82 21832182
2009 Retina-specific GTPase accelerator RGS11/G beta 5S/R9AP is a constitutive heterotrimer selectively targeted to mGluR6 in ON-bipolar neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 78 19625520
1997 The mGluR6 5' upstream transgene sequence directs a cell-specific and developmentally regulated expression in retinal rod and ON-type cone bipolar cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 69 9096137
2008 Allelic variance between GRM6 mutants, Grm6nob3 and Grm6nob4 results in differences in retinal ganglion cell visual responses. The Journal of physiology 66 18687716
2007 Generation, identification and functional characterization of the nob4 mutation of Grm6 in the mouse. Visual neuroscience 61 17430614
1994 Expression of mRNAs of L-AP4-sensitive metabotropic glutamate receptors (mGluR4, mGluR6, mGluR7) in the rat retina. Neuroscience letters 60 8084499
2007 Gbeta5-RGS complexes co-localize with mGluR6 in retinal ON-bipolar cells. The European journal of neuroscience 59 18001285
2000 Regulation of the on bipolar cell mGluR6 pathway by Ca2+. The Journal of neuroscience : the official journal of the Society for Neuroscience 59 10844016
2014 GPR179 is required for high sensitivity of the mGluR6 signaling cascade in depolarizing bipolar cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 57 24790204
2007 A novel connection between rods and ON cone bipolar cells revealed by ectopic metabotropic glutamate receptor 7 (mGluR7) in mGluR6-deficient mouse retinas. The Journal of neuroscience : the official journal of the Society for Neuroscience 54 17553999
2011 mGluR6 deletion renders the TRPM1 channel in retina inactive. Journal of neurophysiology 53 22131384
2016 AAV-mediated transduction and targeting of retinal bipolar cells with improved mGluR6 promoters in rodents and primates. Gene therapy 49 27115727
1997 Impairment of pupillary responses and optokinetic nystagmus in the mGluR6-deficient mouse. Neuropharmacology 49 9144650
1997 (S)-homo-AMPA, a specific agonist at the mGlu6 subtype of metabotropic glutamic acid receptors. Journal of medicinal chemistry 45 9357538
1997 Cloning, distribution and functional expression of the human mGlu6 metabotropic glutamate receptor. Neuropharmacology 40 9144651
2004 Desensitization of the mGluR6 transduction current in tiger salamander On bipolar cells. The Journal of physiology 36 15146044
2011 A phenotypic study of congenital stationary night blindness (CSNB) associated with mutations in the GRM6 gene. Acta ophthalmologica 33 22008250
2009 Sequence variations of GRM6 in patients with high myopia. Molecular vision 26 19862333
2002 Regulation of the retinal bipolar cell mGluR6 pathway by calcineurin. Journal of neurophysiology 24 12205131
2010 Response to methadone maintenance treatment is associated with the MYOCD and GRM6 genes. Molecular diagnosis & therapy 23 20560679
2008 Photopic electroretinograms of mGluR6-deficient mice. Current eye research 22 18214746
2009 Isolation of ON bipolar cell genes via hrGFP-coupled cell enrichment using the mGluR6 promoter. Journal of biochemistry 21 19270057
2009 Membrane anchor R9AP potentiates GTPase-accelerating protein activity of RGS11 x Gbeta5 complex and accelerates inactivation of the mGluR6-G(o) signaling. The Journal of biological chemistry 21 20007977
2011 mGluR6 transcripts in non-neuronal tissues. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 20 22034516
2021 The mGluR6 ligand-binding domain, but not the C-terminal domain, is required for synaptic localization in retinal ON-bipolar cells. The Journal of biological chemistry 19 34793838
2014 Localization of Cacna1s to ON bipolar dendritic tips requires mGluR6-related cascade elements. Investigative ophthalmology & visual science 19 24519419
1997 A late ON response remains in visual response of the mGluR6-deficient mouse. Neuroscience letters 19 9350851
2006 G protein coupling profile of mGluR6 and expression of G alpha proteins in retinal ON bipolar cells. Visual neuroscience 18 17266783
2015 Identification of a new mutant allele, Grm6(nob7), for complete congenital stationary night blindness. Visual neuroscience 17 26241901
2017 A missense mutation in Grm6 reduces but does not eliminate mGluR6 expression or rod depolarizing bipolar cell function. Journal of neurophysiology 16 28490646
1998 CREB-induced transcriptional activation depends on mGluR6 in rod bipolar cells. Brain research. Molecular brain research 16 9675422
2021 Restoration of mGluR6 Localization Following AAV-Mediated Delivery in a Mouse Model of Congenital Stationary Night Blindness. Investigative ophthalmology & visual science 15 33729473
2018 Different Activity Patterns in Retinal Ganglion Cells of TRPM1 and mGluR6 Knockout Mice. BioMed research international 15 29854741
2014 Effects of mGluR6-deficiency on photoreceptor ribbon synapse formation: comparison of electron microscopic analysis of serial sections with random sections. Visual neuroscience 15 24801622
2020 Whole-genome sequencing identifies missense mutation in GRM6 as the likely cause of congenital stationary night blindness in a Tennessee Walking Horse. Equine veterinary journal 14 32654228
2016 Lack of mGluR6-related cascade elements leads to retrograde trans-synaptic effects on rod photoreceptor synapses via matrix-associated proteins. The European journal of neuroscience 14 27037829
2009 Altered G-protein coupling in an mGluR6 point mutant associated with congenital stationary night blindness. Molecular pharmacology 13 19666700
2001 Alternative splicing of mGlu6 gene generates a truncated glutamate receptor in rat retina. Neuroreport 11 11522953
2012 Mutation screening of TRPM1, GRM6, NYX and CACNA1F genes in patients with congenital stationary night blindness. International journal of molecular medicine 10 22735794
2024 Complex N-glycosylation of mGluR6 is required for trans-synaptic interaction with ELFN adhesion proteins. The Journal of biological chemistry 9 38428819
2019 Pseudodominant inheritance of autosomal recessive congenital stationary night blindness in one family with three co-segregating deleterious GRM6 variants identified by next-generation sequencing. Molecular genetics & genomic medicine 9 31677249
2008 The mGlu(4) receptor allosteric modulator N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxamide acts as a direct agonist at mGlu(6) receptors. European journal of pharmacology 9 18593581
2021 Optogenetic control of neural differentiation in Opto-mGluR6 engineered retinal pigment epithelial cell line and mesenchymal stem cells. Journal of cellular biochemistry 8 33847009
2020 Involvement of the C-terminal domain in cell surface localization and G-protein coupling of mGluR6. Journal of neurochemistry 8 33067823
2018 Impacts of GRIN3A, GRM6 and TPH2 genetic polymorphisms on quality of life in methadone maintenance therapy population. PloS one 8 30059533
2015 Mutations in GRM6 identified in consanguineous Pakistani families with congenital stationary night blindness. Molecular vision 8 26628857
2024 Defective glycosylation and ELFN1 binding of mGluR6 congenital stationary night blindness mutants. Life science alliance 6 39681475
2023 Additional evidence supports GRM6 p.Thr178Met as a cause of congenital stationary night blindness in three horse breeds. Veterinary ophthalmology 6 37815029
2014 [Association of ZNF644, GRM6 and CTNND2 genes polymorphisms with high myopia]. Zhonghua yi xue za zhi 4 25142846
2019 Reduced expression of the nob8 gene does not normalize the distribution or function of mGluR6 in the mouse retina. Molecular vision 3 32025181
2024 Compound heterozygous mutations in GRM6 causing complete Schubert-Bornschein type congenital stationary night blindness. Heliyon 2 38434377
2024 Engineered red Opto-mGluR6 Opsins, a red-shifted optogenetic excitation tool, an in vitro study. PloS one 2 39446870
2023 The intracellular C-terminal domain of mGluR6 contains ER retention motifs. Molecular and cellular neurosciences 2 37352898
2019 Effect and mechanism of mGluR6 on the biological function of rat embryonic neural stem cells. Bioscience, biotechnology, and biochemistry 2 30739574
2025 Trans-synaptic Interaction with mGluR6 Contributes to ELFN1 Presynaptic Enrichment in Rod Photoreceptors. The Journal of neuroscience : the official journal of the Society for Neuroscience 1 40930976
2024 Differential Localization and Functional Roles of mGluR6 Paralogs in Zebrafish Retina. Investigative ophthalmology & visual science 1 39475940
2026 CryoEM structure of mGlu6 captures receptor activation prior to G protein coupling. Nature communications 0 41803130
2026 mGluR6 coordinates cone terminal targeting and synaptic layer assembly during human retinal development. bioRxiv : the preprint server for biology 0 42094404
2026 N-Glycosylation of mGluR6 Modulates Receptor Cell-Surface Transport, G-Protein Coupling, and Interactions With Synaptic Adhesion Molecules. Journal of molecular neuroscience : MN 0 42201444
2025 Novel Grm6 Variant in a no b-wave (nob) Mouse Model: Phenotype Characterization and Gene Therapy. Investigative ophthalmology & visual science 0 40923695
2025 The extracellular domain of mGluR6 regulates targeting to the conventional secretion pathway. Molecular and cellular neurosciences 0 41448371
2025 System biology analysis reveals that Grm6 is associated with glutamate accumulation-induced scotopic vision impairment in diabetic mice. Molecular vision 0 41867370

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