Details for: KCNK2

Gene ID: 3776

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: KCNK2

Ensembl ID: ENSG00000082482

Description: potassium two pore domain channel subfamily K member 2

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • L6b glutamatergic cortical neuron CL4023038
    CSI 11.08
    rCSI 34.61%
    PRS 96.76
  • pvalb GABAergic cortical interneuron CL4023018
    CSI 7.69
    rCSI 9.57%
    PRS 96.33
  • sst GABAergic cortical interneuron CL4023017
    CSI 6.07
    rCSI 7.83%
    PRS 97.18
  • inhibitory interneuron CL0000498
    CSI 5.83
    rCSI 13.46%
    PRS 96.86
  • VIP GABAergic cortical interneuron CL4023016
    CSI 5.49
    rCSI 6.55%
    PRS 96.67
  • GABAergic neuron CL0000617
    CSI 4.34
    rCSI 14.53%
    PRS 94.57
  • peripheral nervous system neuron CL2000032
    CSI 4.18
    rCSI 5.69%
    PRS 97.95
  • vascular leptomeningeal cell CL4023051
    CSI 3.86
    rCSI 6.77%
    PRS 98
  • glutamatergic neuron CL0000679
    CSI 3.6
    rCSI 7.39%
    PRS 94.79
  • basal cell of epidermis CL0002187
    CSI 2.83
    rCSI 5.01%
    PRS 87.18
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 2.31
    rCSI 5.62%
    PRS 95.74
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 2.22
    rCSI 7.3%
    PRS 95.25
  • melanocyte of skin CL1000458
    CSI 1.93
    rCSI 2.63%
    PRS 88.49
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 1.81
    rCSI 10.65%
    PRS 96.3
  • L4 intratelencephalic projecting glutamatergic neuron CL4030063
    CSI 1.77
    rCSI 4.24%
    PRS 95.68
  • direct pathway medium spiny neuron CL4023026
    CSI 1.72
    rCSI 41.14%
    PRS 95.1
  • indirect pathway medium spiny neuron CL4023029
    CSI 1.7
    rCSI 41.01%
    PRS 94.91
  • medium spiny neuron CL1001474
    CSI 1.46
    rCSI 12.61%
    PRS 96.61
  • brain vascular cell CL4023072
    CSI 1.37
    rCSI 14.16%
    PRS 96.45
  • central nervous system neuron CL2000029
    CSI 0.88
    rCSI 6.45%
    PRS 97.13
  • starburst amacrine cell CL0004232
    CSI 0.83
    rCSI 7%
    PRS 93.4

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 [KCNK2](/details-gene/3776), also known as TREK-1, encodes the potassium two pore domain channel subfamily K member 2. This protein functions as a mechanosensitive, outwardly rectifying potassium "leak" channel that plays a fundamental role in establishing the resting membrane potential of excitable cells. Expression data indicates that [KCNK2](/details-gene/3776) is a gene of profound significance within the central nervous system. **Overall**, it exhibits its highest cell-type specificity and abundance in various cortical neuronal subtypes, including both excitatory `L6b glutamatergic cortical neuron` ([CL4023038](/details-cell/CL4023038)) and inhibitory `pvalb GABAergic cortical interneuron` ([CL4023018](/details-cell/CL4023018)), suggesting a critical role in regulating neuronal excitability and maintaining network homeostasis. Its function is modulated by a wide range of physical and chemical stimuli, including membrane stretch, intracellular pH, and signaling lipids, and it is implicated in processes ranging from sensory perception to cardiac function. ## Cellular Roles and Expression Landscape The expression profile of [KCNK2](/details-gene/3776) strongly establishes its identity as a key regulator of the neuronal milieu. **Overall**, the gene shows its most significant expression in a diverse set of cortical neurons. It is the top marker for `L6b glutamatergic cortical neuron` ([CL4023038](/details-cell/CL4023038)) (CSI: 11.08), and also shows very high significance in inhibitory interneuron populations such as `pvalb GABAergic cortical interneuron` ([CL4023018](/details-cell/CL4023018)) (CSI: 7.69) and `sst GABAergic cortical interneuron` ([CL4023017](/details-cell/CL4023017)) (CSI: 6.07). This broad but potent expression across both primary excitatory (`glutamatergic neuron` ([CL0000679](/details-cell/CL0000679))) and inhibitory (`GABAergic neuron` ([CL0000617](/details-cell/CL0000617))) arms of cortical circuits suggests a fundamental role in setting the global threshold for action potential firing and stabilizing synaptic transmission. While its primary role appears to be neuronal, [KCNK2](/details-gene/3776) also shows moderate significance in non-neuronal cell types like `vascular leptomeningeal cell` ([CL4023051](/details-cell/CL4023051)) and `basal cell of epidermis` ([CL0002187](/details-cell/CL0002187)). This hints at broader physiological functions, potentially related to mechanosensation or ion homeostasis in non-excitable tissues. The absence of immune or hematopoietic cells from the top-expressed list further refines its role as being predominantly localized to the nervous and structural tissues. ## Pathways and Molecular Function The molecular functions and pathway involvements of [KCNK2](/details-gene/3776) are highly consistent with its cellular expression profile. As a core component of the `Tandem pore domain potassium channels` ([R-HSA-1296346](https://reactome.org/content/detail/R-HSA-1296346)) and `Potassium channels` ([R-HSA-1296071](https://reactome.org/content/detail/R-HSA-1296071)) in general, its primary molecular function is `Potassium ion leak channel activity` ([GO:0022841](https://www.ebi.ac.uk/QuickGO/term/GO:0022841)). This function is essential for the `Neuronal system` ([R-HSA-112316](https://reactome.org/content/detail/R-HSA-112316)), where it helps establish the `Phase 4 - resting membrane potential` ([R-HSA-5576886](https://reactome.org/content/detail/R-HSA-5576886)) that keeps neurons in a quiescent state until they are appropriately stimulated. The gene product's annotated role in `Neuronal action potential` ([GO:0019228](https://www.ebi.ac.uk/QuickGO/term/GO:0019228)) and `Chemical synaptic transmission, postsynaptic` ([GO:0099565](https://www.ebi.ac.uk/QuickGO/term/GO:0099565)) directly explains its high significance in cortical neurons. Furthermore, its specific annotation for `Mechanosensitive potassium channel activity` ([GO:0098782](https://www.ebi.ac.uk/QuickGO/term/GO:0098782)) is a key feature, connecting cellular membrane tension to electrical activity, a process critical for sensory functions like touch ([GO:0050976](https://www.ebi.ac.uk/QuickGO/term/GO:0050976)) and potentially for neuronal responses to osmotic stress or cell swelling. A recent study confirmed its role in tension activation [Link](https://doi.org/10.1038/s41467-024-47208-5). Although not highlighted in the provided expression data, its involvement in `Cardiac conduction` ([R-HSA-5576891](https://reactome.org/content/detail/R-HSA-5576891)) and `Muscle contraction` ([R-HSA-397014](https://reactome.org/content/detail/R-HSA-397014)) suggests important, albeit potentially more context-specific, roles in cardiovascular and musculoskeletal systems, which is supported by reports linking related proteins to muscular dystrophy and arrhythmia [Link](https://doi.org/10.1172/jci79562). ## Research Directions The critical role of [KCNK2](/details-gene/3776) in setting neuronal resting potential, combined with its high expression in specific neuronal subtypes, makes it a gene of significant clinical and scientific interest. Research has already linked loss-of-function mutations to neuronal hyperexcitability in conditions like migraine [Link](https://doi.org/10.1016/j.neuron.2018.11.039). Based on the available data, several testable hypotheses can be formulated. 1. **Hypothesis of Layer-Specific Vulnerability:** The exceptionally high significance of [KCNK2](/details-gene/3776) in deep-layer cortical neurons, particularly `L6b glutamatergic cortical neuron` ([CL4023038](/details-cell/CL4023038)), suggests that these cells may be disproportionately affected by [KCNK2](/details-gene/3776) channelopathies. We hypothesize that migraine-associated mutations in [KCNK2](/details-gene/3776) cause a more pronounced reduction in the action potential threshold and a greater increase in spontaneous firing in layer 6b neurons compared to neurons in other cortical layers, potentially creating a focal point for the initiation of cortical spreading depression. 2. **Hypothesis of Differential Modulation:** Given its expression in both excitatory and inhibitory neurons, we hypothesize that the activity of the [KCNK2](/details-gene/3776) channel is differentially regulated by local signaling molecules (e.g., arachidonic acid, as suggested by [GO:1904551](https://www.ebi.ac.uk/QuickGO/term/GO:1904551)) in these opposing cell types. This differential modulation may serve as a homeostatic mechanism to maintain the excitation/inhibition balance within cortical microcircuits. To investigate the **Hypothesis of Layer-Specific Vulnerability**, a key experiment would involve using a CRISPR/Cas9-engineered mouse model carrying a known human migraine-associated [KCNK2](/details-gene/3776) mutation. Acute cortical slices could be prepared from both mutant and wild-type mice. Using patch-clamp electrophysiology combined with morphological identification or post-hoc staining, recordings could be specifically targeted to `L6b glutamatergic cortical neuron` ([CL4023038](/details-cell/CL4023038)) and, for comparison, upper-layer pyramidal neurons. A direct comparison of intrinsic properties such as resting membrane potential, input resistance, and firing frequency in response to depolarizing current steps would directly test whether the mutation confers a cell-type-specific hyperexcitable phenotype. Therapeutically, [KCNK2](/details-gene/3776) represents a promising target for conditions characterized by neuronal hyperexcitability, such as epilepsy and migraine. Since loss-of-function is associated with pathology, the therapeutic strategy would be **activation** of the channel. Small molecule agonists or positive allosteric modulators that enhance the channel's open probability could restore the hyperpolarizing leak current and stabilize the neuronal membrane potential. However, its broad expression in the CNS and its known sensitivity to anesthetics [Link](https://doi.org/10.1038/8084) raise the possibility of significant side effects, such as sedation. Therefore, developing activators with specificity for certain channel conformations or delivering them to targeted neural circuits would be critical for clinical translation.

Genular Protein ID: 1042329577

Symbol: KCNK2_HUMAN

Name: Potassium channel subfamily K member 2

UniProtKB Accession Codes:

O95069 A1Z1V3 A8K618 B2RCS4 B7ZL56 D3DTA5 Q5DP47 Q5DP48 Q9NRT2 Q9UNE3

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 3 CTD 1 ChEBI 19 ChEMBL 1 ChiTaRS 1 DNASU 1 DisGeNET 1 DrugBank 2 DrugCentral 1 EMBL 18 Ensembl 4 EvolutionaryTrace 1 ExpressionAtlas 1 GO 24 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 InterPro 3 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 1 PDBsum 1 PRINTS 2 PRO 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 RNAct 1 Reactome 2 RefSeq 4 Rhea 5 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 10321245

Title: Inhalational anesthetics activate two-pore-domain background K+ channels.

PubMed ID: 10321245

DOI: 10.1038/8084

PubMed ID: 10784345

Title: Cloning, localisation and functional expression of the human orthologue of the TREK-1 potassium channel.

PubMed ID: 10784345

DOI: 10.1007/s004249900235

PubMed ID: 24196565

Title: A splice variant of the two-pore domain potassium channel TREK-1 with only one pore domain reduces the surface expression of full-length TREK-1 channels.

PubMed ID: 24196565

DOI: 10.1007/s00424-013-1384-z

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

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: 11319556

Title: KCNK2: reversible conversion of a hippocampal potassium leak into a voltage-dependent channel.

PubMed ID: 11319556

DOI: 10.1038/87434

PubMed ID: 23169818

Title: SUMOylation silences heterodimeric TASK potassium channels containing K2P1 subunits in cerebellar granule neurons.

PubMed ID: 23169818

DOI: 10.1126/scisignal.2003431

PubMed ID: 26642364

Title: POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking.

PubMed ID: 26642364

DOI: 10.1172/jci79562

PubMed ID: 30573346

Title: Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK.

PubMed ID: 30573346

DOI: 10.1016/j.neuron.2018.11.039

PubMed ID: 38605031

Title: Tension activation of mechanosensitive two-pore domain K+ channels TRAAK, TREK-1, and TREK-2.

PubMed ID: 38605031

DOI: 10.1038/s41467-024-47208-5

Sequence Information:

  • Length: 426
  • Mass: 47093
  • Checksum: DB10382B1803DA13
  • Sequence:
    • MLPSASRERP GYRAGVAAPD LLDPKSAAQN SKPRLSFSTK PTVLASRVES DTTINVMKWK 
TVSTIFLVVV LYLIIGATVF KALEQPHEIS QRTTIVIQKQ TFISQHSCVN STELDELIQQ 
IVAAINAGII PLGNTSNQIS HWDLGSSFFF AGTVITTIGF GNISPRTEGG KIFCIIYALL 
GIPLFGFLLA GVGDQLGTIF GKGIAKVEDT FIKWNVSQTK IRIISTIIFI LFGCVLFVAL 
PAIIFKHIEG WSALDAIYFV VITLTTIGFG DYVAGGSDIE YLDFYKPVVW FWILVGLAYF 
AAVLSMIGDW LRVISKKTKE EVGEFRAHAA EWTANVTAEF KETRRRLSVE IYDKFQRATS 
IKRKLSAELA GNHNQELTPC RRTLSVNHLT SERDVLPPLL KTESIYLNGL TPHCAGEEIA 
VIENIK

Genular Protein ID: 782303559

Symbol: U3N6F0_HUMAN

Name: N/A

UniProtKB Accession Codes:

U3N6F0

Database IDs:

ARBA 6 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 ExpressionAtlas 1 GO 4 Gene3D 1 HOGENOM 1 InterPro 3 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 2 Pfam 2 RefSeq 1 RuleBase 1 SAM 1 SMR 1 SUPFAM 1 UCSC 1 VEuPathDB 1

Sequence Information:

  • Length: 411
  • Mass: 45495
  • Checksum: FDE40CAB21B42A1C
  • Sequence:
    • MAAPDLLDPK SAAQNSKPRL SFSTKPTVLA SRVESDTTIN VMKWKTVSTI FLVVVLYLII 
GATVFKALEQ PHEISQRTTI VIQKQTFISQ HSCVNSTELD ELIQQIVAAI NAGIIPLGNT 
SNQISHWDLG SSFFFAGTVI TTIGFGNISP RTEGGKIFCI IYALLGIPLF GFLLAGVGDQ 
LGTIFGKGIA KVEDTFIKWN VSQTKIRIIS TIIFILFGCV LFVALPAIIF KHIEGWSALD 
AIYFVVITLT TIGFGDYVAG GSDIEYLDFY KPVVWFWILV GLAYFAAVLS MIGDWLRVIS 
KKTKEEVGEF RAHAAEWTAN VTAEFKETRR RLSVEIYDKF QRATSIKRKL SAELAGNHNQ 
ELTPCRRTLS VNHLTSERDV LPPLLKTESI YLNGLTPHCA GEEIAVIENI K

Genular Protein ID: 2967993962

Symbol: U3N834_HUMAN

Name: N/A

UniProtKB Accession Codes:

U3N834

Database IDs:

ARBA 6 AlphaFoldDB 1 Antibodypedia 1 BioGRID-ORCS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 2 ExpressionAtlas 1 GO 4 Gene3D 1 InterPro 3 NCBI Taxonomy 1 OrthoDB 1 PANTHER 2 PRINTS 2 Pfam 2 RefSeq 2 RuleBase 1 SAM 1 SMR 1 SUPFAM 1 UCSC 1 VEuPathDB 1

Sequence Information:

  • Length: 422
  • Mass: 46888
  • Checksum: 1AD4E0B5C1B6CBE7
  • Sequence:
    • MMNPRAKRDF YLAAPDLLDP KSAAQNSKPR LSFSTKPTVL ASRVESDTTI NVMKWKTVST 
IFLVVVLYLI IGATVFKALE QPHEISQRTT IVIQKQTFIS QHSCVNSTEL DELIQQIVAA 
INAGIIPLGN TSNQISHWDL GSSFFFAGTV ITTIGFGNIS PRTEGGKIFC IIYALLGIPL 
FGFLLAGVGD QLGTIFGKGI AKVEDTFIKW NVSQTKIRII STIIFILFGC VLFVALPAII 
FKHIEGWSAL DAIYFVVITL TTIGFGDYVA GGSDIEYLDF YKPVVWFWIL VGLAYFAAVL 
SMIGDWLRVI SKKTKEEVGE FRAHAAEWTA NVTAEFKETR RRLSVEIYDK FQRATSIKRK 
LSAELAGNHN QELTPCRRTL SVNHLTSERD VLPPLLKTES IYLNGLTPHC AGEEIAVIEN 
IK

Genular Protein ID: 3940273243

Symbol: Q6ZW95_HUMAN

Name: N/A

UniProtKB Accession Codes:

Q6ZW95

Database IDs:

Bgee 1 BioGRID-ORCS 1 CTD 1 ChiTaRS 1 DNASU 1 DisGeNET 1 EMBL 5 Ensembl 2 GO 2 Gene3D 1 GeneTree 1 HGNC 1 HOGENOM 1 InterPro 1 KEGG 1 NCBI Taxonomy 1 OrthoDB 1 PRINTS 1 PeptideAtlas 1 PharmGKB 1 Proteomes 2 RefSeq 3 SAM 1 UCSC 1 VEuPathDB 1

Citations:

PubMed ID: 11237011

Title: Initial sequencing and analysis of the human genome.

PubMed ID: 11237011

DOI: 10.1038/35057062

PubMed ID: 15496913

Title: Finishing the euchromatic sequence of the human genome.

PubMed ID: 15496913

DOI: 10.1038/nature03001

PubMed ID: 16710414

Title: The DNA sequence and biological annotation of human chromosome 1.

PubMed ID: 16710414

DOI: 10.1038/nature04727

Sequence Information:

  • Length: 152
  • Mass: 17248
  • Checksum: DC9BF5C52AC672AB
  • Sequence:
    • MMNPRAKRDF YLAAPDLLDP KSAAQNSKPR LSFSTKPTVL ASRVESDTTI NVMKWKTVST 
IFLVVVLYLI IGATVFKALE QPHEISQRTT IVIQKQTFIS QHSCVNSTEL DELIQDLETS 
HHAQKAAKYS VSSMPYWEFP SLVFSWLELE IS