Details for: KCNJ6

Gene ID: 3763

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: KCNJ6

Ensembl ID: ENSG00000157542

Description: potassium inwardly rectifying channel subfamily J member 6

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • pvalb GABAergic cortical interneuron CL4023018
    CSI 34.69
    rCSI 43.16%
    PRS 94.75
  • sst GABAergic cortical interneuron CL4023017
    CSI 33.65
    rCSI 43.38%
    PRS 96
  • sncg GABAergic cortical interneuron CL4023015
    CSI 30.44
    rCSI 48.95%
    PRS 95.32
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 28.15
    rCSI 47.26%
    PRS 95.66
  • VIP GABAergic cortical interneuron CL4023016
    CSI 26.33
    rCSI 31.45%
    PRS 95.38
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 25.52
    rCSI 45.06%
    PRS 95.35
  • L2/3 intratelencephalic projecting glutamatergic neuron CL4030059
    CSI 22.48
    rCSI 48.76%
    PRS 93.31
  • retina horizontal cell CL0000745
    CSI 22.23
    rCSI 33.88%
    PRS 97.3
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 21.65
    rCSI 52.61%
    PRS 94.15
  • chandelier pvalb GABAergic cortical interneuron CL4023036
    CSI 19.3
    rCSI 60.36%
    PRS 95.94
  • L6b glutamatergic cortical neuron CL4023038
    CSI 18.41
    rCSI 57.54%
    PRS 95.53
  • pancreatic A cell CL0000171
    CSI 16.73
    rCSI 17.53%
    PRS 98.5
  • neuroblast (sensu Nematoda and Protostomia) CL0000338
    CSI 16.4
    rCSI 18.94%
    PRS 96.21
  • glioblast CL0000030
    CSI 15.67
    rCSI 25%
    PRS 96.11
  • enteroendocrine cell CL0000164
    CSI 14.99
    rCSI 20.49%
    PRS 97.47
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 14.74
    rCSI 55.7%
    PRS 94.88
  • L5 extratelencephalic projecting glutamatergic cortical neuron CL4023041
    CSI 14.69
    rCSI 52.87%
    PRS 94.55
  • neuron CL0000540
    CSI 13.7
    rCSI 36.49%
    PRS 92.96
  • interneuron CL0000099
    CSI 12.63
    rCSI 25.35%
    PRS 97.1
  • inhibitory interneuron CL0000498
    CSI 12.42
    rCSI 28.67%
    PRS 95.62
  • lung neuroendocrine cell CL1000223
    CSI 12.25
    rCSI 18.12%
    PRS 98.04
  • rod bipolar cell CL0000751
    CSI 12.22
    rCSI 21.97%
    PRS 96.75
  • astrocyte CL0000127
    CSI 11.94
    rCSI 25.44%
    PRS 90.91
  • enteroendocrine cell of small intestine CL0009006
    CSI 11.76
    rCSI 25.9%
    PRS 98.47
  • retinal bipolar neuron CL0000748
    CSI 11.28
    rCSI 21.12%
    PRS 95.91
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 10.43
    rCSI 24.94%
    PRS 94.28
  • cerebral cortex neuron CL0010012
    CSI 10.12
    rCSI 41.25%
    PRS 95.18
  • glycinergic amacrine cell CL4030028
    CSI 10.03
    rCSI 26.14%
    PRS 95.43
  • GABAergic amacrine cell CL4030027
    CSI 9.78
    rCSI 33.49%
    PRS 93.15
  • neural cell CL0002319
    CSI 9.67
    rCSI 36.51%
    PRS 92.97
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 9.21
    rCSI 30.28%
    PRS 93.76
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 9.15
    rCSI 53.89%
    PRS 95.03
  • cerebral cortex endothelial cell CL1001602
    CSI 8.72
    rCSI 15.08%
    PRS 97.05
  • cerebellar granule cell CL0001031
    CSI 8.4
    rCSI 12.35%
    PRS 96.44
  • glutamatergic neuron CL0000679
    CSI 8.15
    rCSI 16.74%
    PRS 93.16
  • amacrine cell CL0000561
    CSI 7.72
    rCSI 22.38%
    PRS 95.64
  • pancreatic D cell CL0000173
    CSI 7.47
    rCSI 7.34%
    PRS 98.5
  • H2 horizontal cell CL0004218
    CSI 5.66
    rCSI 28.14%
    PRS 95.85
  • serotonergic neuron CL0000850
    CSI 5.52
    rCSI 24.65%
    PRS 91.61
  • dopaminergic neuron CL0000700
    CSI 5.44
    rCSI 30.75%
    PRS 94.32
  • type B pancreatic cell CL0000169
    CSI 4.88
    rCSI 10.8%
    PRS 98.18
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 4.66
    rCSI 8.47%
    PRS 96.04
  • GABAergic neuron CL0000617
    CSI 4.59
    rCSI 15.39%
    PRS 92.89
  • central nervous system neuron CL2000029
    CSI 4.27
    rCSI 31.4%
    PRS 95.95
  • type L enteroendocrine cell CL0002279
    CSI 4.01
    rCSI 7.52%
    PRS 98.37
  • H1 horizontal cell CL0004217
    CSI 4
    rCSI 15.83%
    PRS 95.29
  • retinal ganglion cell CL0000740
    CSI 3.74
    rCSI 8.25%
    PRS 95.28
  • Bergmann glial cell CL0000644
    CSI 3.2
    rCSI 4.38%
    PRS 95.87
  • pancreatic PP cell CL0002275
    CSI 2.73
    rCSI 10.88%
    PRS 98.19
  • cerebellar neuron CL1001611
    CSI 2.55
    rCSI 22.43%
    PRS 92.91
  • Cajal-Retzius cell CL0000695
    CSI 2.46
    rCSI 19.25%
    PRS 98.28
  • neuroendocrine cell CL0000165
    CSI 1.65
    rCSI 6.38%
    PRS 98.34
  • pancreatic epsilon cell CL0005019
    CSI 1.33
    rCSI 6.22%
    PRS 98.31
  • midbrain dopaminergic neuron CL2000097
    CSI 1.32
    rCSI 8.49%
    PRS 95.66
  • P/D1 enteroendocrine cell CL0002268
    CSI 0.76
    rCSI 4.13%
    PRS 98.13
  • ON parasol ganglion cell CL4033052
    CSI 0.69
    rCSI 9.81%
    PRS 94.94

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 [KCNJ6](/details-gene/3763) (Potassium Inwardly Rectifying Channel Subfamily J Member 6) encodes the G protein-activated inward rectifier potassium channel 2 (GIRK2 or Kir3.2), a critical component of neuronal and endocrine signaling pathways. **Overall**, this gene exhibits highly specific and significant expression in the central nervous system, particularly within diverse subtypes of GABAergic cortical interneurons and glutamatergic neurons. Functionally, it is integral to the regulation of neuronal excitability through G protein-coupled receptor signaling, primarily by modulating potassium ion flux across the plasma membrane. Mutations in [KCNJ6](/details-gene/3763) are causally linked to Keppen-Lubinsky syndrome ([600877](https://omim.org/entry/600877)), a severe developmental disorder, highlighting its essential role in human neurodevelopment [Link](https://doi.org/10.1016/j.ajhg.2014.12.011). ## Cellular Roles and Expression Landscape The expression profile of [KCNJ6](/details-gene/3763) establishes it as a key regulator of excitable cells, with a pronounced role in the central nervous system. The **Overall** context shows its highest significance in a wide array of inhibitory neurons, including [pvalb GABAergic cortical interneuron](/details-cell/CL4023018) (CSI: 34.69), [sst GABAergic cortical interneuron](/details-cell/CL4023017) (CSI: 33.65), [sncg GABAergic cortical interneuron](/details-cell/CL4023015) (CSI: 30.44), and [VIP GABAergic cortical interneuron](/details-cell/CL4023016) (CSI: 26.33). Its high significance extends to excitatory neurons such as [L2/3 intratelencephalic projecting glutamatergic neuron](/details-cell/CL4030059) (CSI: 22.48), suggesting a broad function in modulating cortical circuitry. Beyond the cortex, [KCNJ6](/details-gene/3763) is a significant marker in other neuronal and neuro-related cell types, including the [retina horizontal cell](/details-cell/CL0000745) and [neuroblast](/details-cell/CL0000338). Notably, the gene also shows significant expression in hormone-secreting cells outside the nervous system, such as the [pancreatic A cell](/details-cell/CL0000171) and the [enteroendocrine cell](/details-cell/CL0000164). This pattern is consistent with early research identifying its expression in pancreatic islets and its role in forming G-protein-activated channels in these cells [Link](https://doi.org/10.1074/jbc.270.44.26086), [Link](https://doi.org/10.2337/diab.44.5.592). The expression in [glioblast](/details-cell/CL0000030) suggests a potential role in glial cell biology or pathology. ## Pathways and Molecular Function The molecular function of [KCNJ6](/details-gene/3763) is well-defined as contributing to '[G-protein activated inward rectifier potassium channel activity](/details-go/GO:0015467)' and '[Potassium ion import across plasma membrane](/details-go/GO:1990573)'. These activities are central to its role in cellular signaling. The Reactome pathway annotations strongly reinforce its role in the nervous system, with involvement in '[Neuronal system](/details-pathway/R-HSA-112316)', '[Transmission across chemical synapses](/details-pathway/R-HSA-112315)', and '[Neurotransmitter receptors and postsynaptic signal transmission](/details-pathway/R-HSA-112314)'. Its high expression in GABAergic interneurons is directly explained by its participation in the '[Activation of gabab receptors](/details-pathway/R-HSA-991365)' pathway. In this process, the activation of G-protein coupled GABA-B receptors leads to the activation of GIRK channels, including those containing the KCNJ6 subunit, causing membrane hyperpolarization and inhibiting neuronal firing. This mechanism is a cornerstone of slow, prolonged synaptic inhibition in the brain. The channel's ability to form heterotetramers with other Kir3 subunits allows for channels with diverse functional properties, enabling fine-tuned regulation of cellular excitability in different contexts [Link](https://doi.org/10.1016/s0898-6568(99)00059-5). ## Research Directions The data highlights [KCNJ6](/details-gene/3763) as a crucial regulator of neuronal and endocrine cell excitability. Its widespread yet specific expression across functionally distinct interneuron subtypes suggests it is a master regulator of inhibitory tone in the cortex. **Proposed Hypotheses:** 1. Given its high significance in multiple, distinct GABAergic interneuron subtypes ([pvalb](/details-cell/CL4023018), [sst](/details-cell/CL4023017), [VIP](/details-cell/CL4023016)), the specific subunit composition and post-translational modification of [KCNJ6](/details-gene/3763)-containing channels may differ between these cell types, leading to distinct biophysical properties that fine-tune the inhibitory control they exert on local circuits. 2. The significant expression of [KCNJ6](/details-gene/3763) in [pancreatic A cells](/details-cell/CL0000171) suggests it plays a critical role in coupling G-protein coupled receptor (GPCR) signaling, likely from metabolic or hormonal cues, to the regulation of glucagon secretion by controlling the cell's membrane potential. **Experimental Approach:** To test the first hypothesis, a combination of molecular and electrophysiological approaches could be employed. Using subtype-specific Cre-driver mouse lines (e.g., Pvalb-Cre, Sst-Cre, Vip-Cre) combined with a floxed *Kcnj6* allele would allow for cell-type-specific knockout of the gene. Whole-cell patch-clamp recordings from identified interneurons in acute brain slices could then be performed to assess changes in intrinsic excitability, resting membrane potential, and the magnitude of the hyperpolarizing current induced by GABA-B receptor agonists. Furthermore, immunoprecipitation of [KCNJ6](/details-gene/3763) from each sorted interneuron population followed by mass spectrometry could identify interacting Kir3 subunits and regulatory proteins, revealing potential differences in channel composition. **Therapeutic Potential:** As an ion channel, [KCNJ6](/details-gene/3763) is a druggable target. However, its critical role in widespread neuronal function and the severe phenotype of Keppen-Lubinsky syndrome ([600877](https://omim.org/entry/600877)) suggest that global inhibition or activation would likely have significant adverse effects. A more promising strategy would be the development of allosteric modulators that could fine-tune channel activity in a circuit-specific manner, potentially for conditions characterized by neuronal hyperexcitability, such as certain forms of epilepsy. Given its role in linking GPCRs to cellular activity, it could also be a target for modulating hormone secretion in metabolic disorders, though the potential for neurological side effects would require careful consideration.

Genular Protein ID: 3252028203

Symbol: KCNJ6_HUMAN

Name: G protein-activated inward rectifier potassium channel 2

UniProtKB Accession Codes:

P48051 Q3MJ74 Q53WW6

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 4 DrugCentral 1 EMBL 8 Ensembl 2 GO 8 Gene3D 2 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 6 KEGG 1 MANE-Select 1 MIM 3 MINT 1 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 Orphanet 1 OrthoDB 1 PANTHER 2 PIR 1 PIRSF 1 PRINTS 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 2 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 2 RefSeq 1 SMR 1 STRING 1 SUPFAM 2 SignaLink 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 7592809

Title: Pancreatic islet cells express a family of inwardly rectifying K+ channel subunits which interact to form G-protein-activated channels.

PubMed ID: 7592809

DOI: 10.1074/jbc.270.44.26086

PubMed ID: 10659995

Title: Co-expression of human Kir3 subunits can yield channels with different functional properties.

PubMed ID: 10659995

DOI: 10.1016/s0898-6568(99)00059-5

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

PubMed ID: 7796919

Title: Characterization and variation of a human inwardly-rectifying-K-channel gene (KCNJ6): a putative ATP-sensitive K-channel subunit.

PubMed ID: 7796919

DOI: 10.1016/0014-5793(95)00498-x

PubMed ID: 7729621

Title: Isolation of a cDNA clone encoding a KATP channel-like protein expressed in insulin-secreting cells, localization of the human gene to chromosome band 21q22.1, and linkage studies with NIDDM.

PubMed ID: 7729621

DOI: 10.2337/diab.44.5.592

PubMed ID: 25620207

Title: Keppen-Lubinsky syndrome is caused by mutations in the inwardly rectifying K+ channel encoded by KCNJ6.

PubMed ID: 25620207

DOI: 10.1016/j.ajhg.2014.12.011

Sequence Information:

  • Length: 423
  • Mass: 48451
  • Checksum: 7A02F6B0FBF8B7D4
  • Sequence:
    • MAKLTESMTN VLEGDSMDQD VESPVAIHQP KLPKQARDDL PRHISRDRTK RKIQRYVRKD 
GKCNVHHGNV RETYRYLTDI FTTLVDLKWR FNLLIFVMVY TVTWLFFGMI WWLIAYIRGD 
MDHIEDPSWT PCVTNLNGFV SAFLFSIETE TTIGYGYRVI TDKCPEGIIL LLIQSVLGSI 
VNAFMVGCMF VKISQPKKRA ETLVFSTHAV ISMRDGKLCL MFRVGDLRNS HIVEASIRAK 
LIKSKQTSEG EFIPLNQTDI NVGYYTGDDR LFLVSPLIIS HEINQQSPFW EISKAQLPKE 
ELEIVVILEG MVEATGMTCQ ARSSYITSEI LWGYRFTPVL TLEDGFYEVD YNSFHETYET 
STPSLSAKEL AELASRAELP LSWSVSSKLN QHAELETEEE EKNLEEQTER NGDVANLENE 
SKV