Details for: GRM8

Gene ID: 2918

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: GRM8

Ensembl ID: ENSG00000179603

Description: glutamate metabotropic receptor 8

Cell Significance Landscape

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • pvalb GABAergic cortical interneuron CL4023018
    CSI 41.22
    rCSI 51.28%
    PRS 97.73
  • vascular leptomeningeal cell CL4023051
    CSI 34.01
    rCSI 59.62%
    PRS 98.84
  • sncg GABAergic cortical interneuron CL4023015
    CSI 27.18
    rCSI 43.72%
    PRS 97.91
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 22.3
    rCSI 25.75%
    PRS 98.57
  • neural crest cell CL0011012
    CSI 21.96
    rCSI 17.36%
    PRS 99.35
  • interneuron CL0000099
    CSI 21.75
    rCSI 43.66%
    PRS 98.76
  • choroid plexus epithelial cell CL0000706
    CSI 21.07
    rCSI 34.5%
    PRS 98.5
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 20.36
    rCSI 34.18%
    PRS 98.18
  • glycinergic amacrine cell CL4030028
    CSI 17.81
    rCSI 46.4%
    PRS 97.85
  • amacrine cell CL0000561
    CSI 17.21
    rCSI 49.88%
    PRS 98.15
  • sst GABAergic cortical interneuron CL4023017
    CSI 16.5
    rCSI 21.28%
    PRS 98.31
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 16.22
    rCSI 58.36%
    PRS 97.66
  • inhibitory interneuron CL0000498
    CSI 16.2
    rCSI 37.39%
    PRS 98.1
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 15.6
    rCSI 37.92%
    PRS 97.28
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 15.42
    rCSI 58.26%
    PRS 97.58
  • retina horizontal cell CL0000745
    CSI 13.52
    rCSI 20.61%
    PRS 99.11
  • epithelial cell CL0000066
    CSI 12.71
    rCSI 19.52%
    PRS 97.35
  • astrocyte of the cerebral cortex CL0002605
    CSI 12.24
    rCSI 27.44%
    PRS 98.15
  • VIP GABAergic cortical interneuron CL4023016
    CSI 11.36
    rCSI 13.57%
    PRS 98.01
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 11.36
    rCSI 27.17%
    PRS 97.3
  • GABAergic amacrine cell CL4030027
    CSI 11.13
    rCSI 38.12%
    PRS 96.96
  • cardiac muscle cell CL0000746
    CSI 10.77
    rCSI 15.46%
    PRS 98.14
  • cerebral cortex endothelial cell CL1001602
    CSI 10.52
    rCSI 18.2%
    PRS 98.73
  • kidney connecting tubule epithelial cell CL1000768
    CSI 10.31
    rCSI 26.16%
    PRS 99.02
  • parietal epithelial cell CL1000452
    CSI 10.28
    rCSI 27.49%
    PRS 99.1
  • neural cell CL0002319
    CSI 9.73
    rCSI 36.72%
    PRS 96.59
  • glial cell CL0000125
    CSI 9.18
    rCSI 34.96%
    PRS 98.02
  • Bergmann glial cell CL0000644
    CSI 8.74
    rCSI 11.95%
    PRS 98.4
  • glutamatergic neuron CL0000679
    CSI 8.06
    rCSI 16.56%
    PRS 96.48
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 8.06
    rCSI 47.45%
    PRS 97.7
  • retinal ganglion cell CL0000740
    CSI 7.54
    rCSI 16.66%
    PRS 97.98
  • central nervous system neuron CL2000029
    CSI 7.4
    rCSI 54.42%
    PRS 98.32
  • dopaminergic neuron CL0000700
    CSI 7.31
    rCSI 41.3%
    PRS 97.44
  • GABAergic neuron CL0000617
    CSI 6.99
    rCSI 23.42%
    PRS 96.31
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 6.92
    rCSI 15.01%
    PRS 96.72
  • serotonergic neuron CL0000850
    CSI 6.63
    rCSI 29.64%
    PRS 96.04
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 6.41
    rCSI 9.09%
    PRS 99.25
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 6.01
    rCSI 15.55%
    PRS 99.37
  • kidney loop of Henle thick ascending limb epithelial cell CL1001106
    CSI 5.69
    rCSI 49.19%
    PRS 98.68
  • starburst amacrine cell CL0004232
    CSI 5.64
    rCSI 47.45%
    PRS 95.98
  • regular ventricular cardiac myocyte CL0002131
    CSI 5.22
    rCSI 32.6%
    PRS 98.34
  • kidney collecting duct intercalated cell CL1001432
    CSI 5.15
    rCSI 36.78%
    PRS 98.3
  • renal beta-intercalated cell CL0002201
    CSI 5.12
    rCSI 12.21%
    PRS 99.47
  • brain vascular cell CL4023072
    CSI 4.83
    rCSI 49.96%
    PRS 98.35
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 4.55
    rCSI 8.27%
    PRS 98.42
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 4.19
    rCSI 13.76%
    PRS 96.92
  • basket cell CL0000118
    CSI 3.78
    rCSI 23.68%
    PRS 94.35
  • diffuse bipolar 6 cell CL4033032
    CSI 3.59
    rCSI 18.85%
    PRS 96.65
  • hepatocyte CL0000182
    CSI 3.49
    rCSI 6.25%
    PRS 98.87
  • medium spiny neuron CL1001474
    CSI 3.48
    rCSI 29.94%
    PRS 97.94
  • L6b glutamatergic cortical neuron CL4023038
    CSI 2.7
    rCSI 8.44%
    PRS 97.98
  • ON parasol ganglion cell CL4033052
    CSI 2.69
    rCSI 38.21%
    PRS 97.82
  • direct pathway medium spiny neuron CL4023026
    CSI 2.47
    rCSI 59.07%
    PRS 96.77
  • indirect pathway medium spiny neuron CL4023029
    CSI 2.44
    rCSI 58.87%
    PRS 96.7
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 2.15
    rCSI 3.8%
    PRS 98.02
  • blood vessel smooth muscle cell CL0019018
    CSI 1.78
    rCSI 14.49%
    PRS 99.52
  • OFF midget ganglion cell CL4033047
    CSI 1.18
    rCSI 23.95%
    PRS 97.77

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary [GRM8](/details-gene/2918) (glutamate metabotropic receptor 8) is a protein-coding gene located on human chromosome 7q31.33 [[Link](https://pubmed.ncbi.nlm.nih.gov/9299241/)]. It encodes the metabotropic glutamate receptor 8 (mGluR8), a member of the group III metabotropic glutamate receptors [[Link](https://doi.org/10.1016/s0169-328x(97)00277-5/)]. As a G protein-coupled receptor (GPCR), [GRM8](/details-gene/2918) is primarily localized to the [plasma membrane](/details-go/GO:0005886) and functions by inhibiting adenylate cyclase through G alpha (i) signaling pathways. Expression data indicates a highly specialized role within the central nervous system, with significant expression in various neuronal subtypes, particularly inhibitory [interneurons](/details-cell/CL0000099), suggesting a critical function in modulating synaptic transmission and neuronal excitability. The gene has a clinical association with OMIM entry [601116](https://omim.org/entry/601116). ## Cellular Roles and Expression Landscape The expression profile of [GRM8](/details-gene/2918) strongly points to a specialized function in the central nervous system, particularly in regulating neuronal circuits. **Overall**, the gene shows the highest significance in various subtypes of inhibitory neurons. It is a top marker for [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 41.22), [sncg GABAergic cortical interneuron](/details-cell/CL4023015) (CSI: 27.18), and other GABAergic subtypes like [lamp5](/details-cell/CL4023011) and [sst](/details-cell/CL4023017) interneurons. This pattern is consistent with a role as a presynaptic autoreceptor that negatively regulates neurotransmitter release, a known function for group III mGluRs. Its high significance in glutamatergic neurons, such as [L5 extratelencephalic projecting glutamatergic cortical neuron](/details-cell/CL4023041) and [L2/3-6 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4023040), further suggests its involvement as a key modulator of both excitatory and inhibitory signaling. Beyond canonical neuronal populations, [GRM8](/details-gene/2918) is also a significant marker in cells associated with the brain's protective layers and fluid systems, including [vascular leptomeningeal cell](/details-cell/CL4023051) and [choroid plexus epithelial cell](/details-cell/CL0000706). This suggests potential roles in sensing glutamate levels at the brain's boundaries, possibly influencing blood-brain barrier function or cerebrospinal fluid homeostasis. Furthermore, its expression in retinal cells like [glycinergic amacrine cell](/details-cell/CL4030028) indicates a role in visual processing, consistent with its annotated function in [visual perception](/details-go/GO:0007601). ## Pathways and Molecular Function The molecular function of [GRM8](/details-gene/2918) is centered on its identity as a [Group iii metabotropic glutamate receptor](/details-go/GO:0001642). It participates in the [Class c/3 (metabotropic glutamate/pheromone receptors)](https://reactome.org/content/detail/R-HSA-420499) family of GPCRs. Upon binding its ligand, glutamate, [GRM8](/details-gene/2918) initiates a signaling cascade characteristic of inhibitory G proteins. Specifically, it is a key component of the [Adenylate cyclase-inhibiting g protein-coupled glutamate receptor signaling pathway](/details-go/GO:0007196). This is achieved through its interaction with inhibitory G-proteins, as detailed in the [G alpha (i) signalling events](/details-pathway/R-HSA-418594) pathway. By inhibiting adenylate cyclase, [GRM8](/details-gene/2918) activation leads to a decrease in intracellular cyclic AMP (cAMP) levels, which in turn modulates the activity of downstream effectors like ion channels and protein kinases. This mechanism is central to its role in the [regulation of synaptic transmission, glutamatergic](/details-go/GO:0051966), where it typically acts presynaptically to reduce glutamate release, thereby preventing neuronal hyperexcitability. ## Research Directions The specific expression pattern and known function of [GRM8](/details-gene/2918) offer several avenues for future investigation, particularly concerning its role in neural circuit modulation and its potential as a therapeutic target. ### Proposed Hypotheses: 1. **Hypothesis 1:** Given its high significance in multiple GABAergic interneuron subtypes ([pvalb GABAergic cortical interneuron](/details-cell/CL4023018), [sncg GABAergic cortical interneuron](/details-cell/CL4023015)), activation of [GRM8](/details-gene/2918) on these cells functions as a presynaptic autoreceptor to suppress GABA release. This would create a disinhibitory effect on principal neurons, providing a mechanism for fine-tuning cortical network gain and synchrony. 2. **Hypothesis 2:** The significant expression of [GRM8](/details-gene/2918) in [choroid plexus epithelial cell](/details-cell/CL0000706) suggests it acts as a sensor for glutamate levels in the cerebrospinal fluid (CSF). Its activation may regulate the transport of molecules or ions across the choroid plexus, thereby contributing to the maintenance of CSF homeostasis and protecting the brain from glutamate excitotoxicity. ### Experimental Approach: To test Hypothesis 1, a combination of genetic manipulation and electrophysiology could be employed. One could utilize a conditional knockout mouse model, crossing a *Grm8*-floxed line with a Pvalb-Cre driver line to specifically delete the gene in parvalbumin-expressing interneurons. By preparing acute cortical slices from these mice and their wild-type littermates, whole-cell patch-clamp recordings from pyramidal neurons could be performed. Optogenetic or electrical stimulation of the Pvalb-interneurons while recording inhibitory postsynaptic currents (IPSCs) in the pyramidal cells would allow for a direct assessment of GABA release. A significant increase in the amplitude or frequency of IPSCs in the knockout animals, especially in response to a group III mGluR agonist, would provide strong evidence that [GRM8](/details-gene/2918) tonically suppresses GABAergic transmission. ### Therapeutic Potential: As a GPCR that modulates neuronal excitability, [GRM8](/details-gene/2918) is a promising therapeutic target. Its primary role in inhibiting neurotransmitter release suggests that **activation** would be the desired therapeutic strategy for conditions characterized by neuronal hyperexcitability, such as epilepsy, anxiety disorders, or neuropathic pain. Positive allosteric modulators (PAMs) or specific agonists for mGluR8 could offer a targeted approach to dampen overactive neural circuits with potentially fewer side effects than broadly acting drugs. The development of such compounds could represent a novel class of neuromodulatory therapeutics.

Genular Protein ID: 1992905438

Symbol: GRM8_HUMAN

Name: Metabotropic glutamate receptor 8

UniProtKB Accession Codes:

O00222 A4D0Y3 B0FZ74 B0M0L0 O15493 O95945 O95946 Q3MIV9 Q52M02 Q6J165

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 2 CDD 2 CORUM 1 CTD 1 ChEBI 5 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 DrugBank 1 DrugCentral 1 EMBL 10 Ensembl 6 ExpressionAtlas 1 GO 9 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 10 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PRINTS 3 PRO 1 PROSITE 4 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 3 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 6 SIGNOR 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 9299241

Title: The human metabotropic glutamate receptor 8 (GRM8) gene: a disproportionately large gene located at 7q31.3-q32.1.

PubMed ID: 9299241

DOI: 10.1006/geno.1997.4842

PubMed ID: 9473604

Title: Group III human metabotropic glutamate receptors 4, 7 and 8: molecular cloning, functional expression, and comparison of pharmacological properties in RGT cells.

PubMed ID: 9473604

DOI: 10.1016/s0169-328x(97)00277-5

PubMed ID: 10216218

Title: Cloning and functional expression of alternative spliced variants of the human metabotropic glutamate receptor 8.

PubMed ID: 10216218

DOI: 10.1016/s0169-328x(99)00050-9

PubMed ID: 12853948

Title: The DNA sequence of human chromosome 7.

PubMed ID: 12853948

DOI: 10.1038/nature01782

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

Sequence Information:

  • Length: 908
  • Mass: 101741
  • Checksum: 95C2D5883DAF6FDE
  • Sequence:
    • MVCEGKRSAS CPCFFLLTAK FYWILTMMQR THSQEYAHSI RVDGDIILGG LFPVHAKGER 
GVPCGELKKE KGIHRLEAML YAIDQINKDP DLLSNITLGV RILDTCSRDT YALEQSLTFV 
QALIEKDASD VKCANGDPPI FTKPDKISGV IGAAASSVSI MVANILRLFK IPQISYASTA 
PELSDNTRYD FFSRVVPPDS YQAQAMVDIV TALGWNYVST LASEGNYGES GVEAFTQISR 
EIGGVCIAQS QKIPREPRPG EFEKIIKRLL ETPNARAVIM FANEDDIRRI LEAAKKLNQS 
GHFLWIGSDS WGSKIAPVYQ QEEIAEGAVT ILPKRASIDG FDRYFRSRTL ANNRRNVWFA 
EFWEENFGCK LGSHGKRNSH IKKCTGLERI ARDSSYEQEG KVQFVIDAVY SMAYALHNMH 
KDLCPGYIGL CPRMSTIDGK ELLGYIRAVN FNGSAGTPVT FNENGDAPGR YDIFQYQITN 
KSTEYKVIGH WTNQLHLKVE DMQWAHREHT HPASVCSLPC KPGERKKTVK GVPCCWHCER 
CEGYNYQVDE LSCELCPLDQ RPNMNRTGCQ LIPIIKLEWH SPWAVVPVFV AILGIIATTF 
VIVTFVRYND TPIVRASGRE LSYVLLTGIF LCYSITFLMI AAPDTIICSF RRVFLGLGMC 
FSYAALLTKT NRIHRIFEQG KKSVTAPKFI SPASQLVITF SLISVQLLGV FVWFVVDPPH 
IIIDYGEQRT LDPEKARGVL KCDISDLSLI CSLGYSILLM VTCTVYAIKT RGVPETFNEA 
KPIGFTMYTT CIIWLAFIPI FFGTAQSAEK MYIQTTTLTV SMSLSASVSL GMLYMPKVYI 
IIFHPEQNVQ KRKRSFKAVV TAATMQSKLI QKGNDRPNGE VKSELCESLE TNTSSTKTTY 
ISYSNHSI