Affinage

KCNJ6

G protein-activated inward rectifier potassium channel 2 · UniProt P48051

Length
423 aa
Mass
48.5 kDa
Annotated
2026-04-28
100 papers in source corpus 34 papers cited in narrative 34 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNJ6 encodes GIRK2 (Kir3.2), a G-protein-gated inwardly rectifying potassium channel subunit that serves as a principal effector of inhibitory postsynaptic signaling downstream of multiple Gi/o-coupled receptors, controlling neuronal excitability, analgesia, synaptic plasticity, and heart rate. GIRK2 assembles as homotetramers or heterotetramers with GIRK1 and GIRK3, and requires simultaneous binding of Gβγ (four subunits, cooperatively) and PIP2 for channel opening, with intracellular Na+ amplifying activation by increasing Gβγ affinity; cholesterol further potentiates activity by stabilizing PIP2 interaction in transmembrane pockets (PMID:21962516, PMID:23739333, PMID:25049222, PMID:27074662, PMID:34433062). Knockout studies establish that GIRK2 mediates GABAB, opioid, α2-adrenergic, muscarinic, and cannabinoid receptor-driven inhibitory K+ currents in neurons of the cerebellum, hippocampus, locus coeruleus, substantia nigra, and spinal cord, and is required for analgesic responses to morphine, clonidine, baclofen, and cannabinoids (PMID:9342388, PMID:12040038, PMID:12493843, PMID:15028774). De novo heterozygous mutations in KCNJ6 cause Keppen-Lubinsky syndrome and hyperkinetic movement disorder through loss of K+ selectivity and constitutive channel activation, while trisomy of KCNJ6 impairs hippocampal synaptic plasticity and contributes to cognitive deficits in Down syndrome models (PMID:25620207, PMID:29852244, PMID:22308328, PMID:28342823).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1996 High

    Establishing that GIRK2 forms native heteromeric channels with GIRK1 in brain resolved the subunit composition question and showed that GIRK2 loss (as in weaver mice) destabilizes GIRK1, indicating obligate co-assembly.

    Evidence Co-immunoprecipitation from multiple brain regions in rat and mouse; immunocytochemistry in weaver mice

    PMID:8929423

    Open questions at the time
    • Stoichiometry of native heteromers not determined
    • Whether GIRK3 also participates in these complexes was unknown
  2. 1996 High

    Characterization of the weaver G156S pore mutation demonstrated that GIRK2 loss of K+ selectivity and gain of Na+ permeability causes cerebellar granule cell death, establishing the first disease mechanism for a GIRK2 channelopathy.

    Evidence Xenopus oocyte electrophysiology with ion substitution; pharmacological rescue of granule cell differentiation in culture

    PMID:8630252 PMID:8706831

    Open questions at the time
    • Whether heteromeric assembly could rescue selectivity in vivo was untested
    • Downstream cell-death pathway from Na+ influx not defined
  3. 1997 High

    GIRK2 knockout eliminated GABAB-activated inward rectifier currents in cerebellar granule cells, establishing GIRK2 as essential for Gi/o-coupled receptor signaling in these neurons.

    Evidence Patch-clamp electrophysiology on cerebellar granule cells from Kcnj6 knockout mice

    PMID:9342388

    Open questions at the time
    • Whether other brain regions retained residual GIRK currents was not assessed
    • Behavioral consequences of knockout not yet characterized
  4. 1999 High

    Linked concatemer experiments defined how subunit arrangement within GIRK1/GIRK2 tetramers determines ion selectivity, while discovery of region-specific homomeric GIRK2 channels in substantia nigra dopamine neurons revealed tissue-dependent subunit composition.

    Evidence Linked tetramer constructs in oocytes; immunoprecipitation from substantia nigra tissue; PSD-95 binding of Kir3.2c splice variant

    PMID:10493734 PMID:9920664

    Open questions at the time
    • Structural basis for subunit arrangement effects on selectivity filter unknown
    • PDZ-mediated targeting mechanism not fully elucidated
  5. 2002 High

    Systematic pharmacological challenges in GIRK2-null mice established that multiple inhibitory GPCR pathways (opioid, adrenergic, muscarinic, GABAB, cannabinoid) converge on GIRK2 for antinociception, and that GIRK2 mediates the majority of opioid hyperpolarization in locus coeruleus neurons.

    Evidence Hot-plate and spinal reflex behavioral testing in GIRK2-null and GIRK2/GIRK3 double-knockout mice with multiple receptor agonists; brain slice patch-clamp

    PMID:12040038 PMID:12493843 PMID:12496346

    Open questions at the time
    • Central vs. peripheral site of action not distinguished
    • Molecular basis of sex differences in GIRK2-dependent pain sensitivity unknown
  6. 2003 High

    Mapping Gβγ binding to N-terminal and C-terminal segments of GIRK2, and identifying leucine residues critical for gating but not binding, separated the Gβγ docking step from the conformational change that opens the channel.

    Evidence Pulldown/direct binding assays with GIRK2 fragments; mutagenesis; Xenopus oocyte electrophysiology

    PMID:12743112

    Open questions at the time
    • Atomic-resolution contacts between Gβγ and channel awaited structural determination
    • Whether the same residues are critical in heteromeric channels was untested
  7. 2006 High

    Nanoscale immunolabeling revealed that GIRK2 and GABAB receptors co-cluster on dendritic spines near excitatory synapses but are segregated on dendritic shafts, establishing compartment-dependent receptor-channel coupling in hippocampal pyramidal neurons.

    Evidence SDS-digested freeze-fracture replica immunolabeling; quantitative immunogold analysis

    PMID:16624949

    Open questions at the time
    • Mechanisms governing differential clustering in spines vs. shafts unknown
    • Functional consequence of segregation on shafts not demonstrated electrophysiologically
  8. 2011 High

    Crystal structures of GIRK2 in multiple states revealed dual gating (G loop gate and inner helix gate), showed PIP2 couples the two gates, and identified the Na+ binding site, providing an atomic framework for understanding coincidence detection of Gβγ, PIP2, and Na+.

    Evidence X-ray crystallography of wild-type and constitutively active GIRK2 with and without PIP2

    PMID:21962516

    Open questions at the time
    • Structures lacked Gβγ; the full ternary complex was unresolved
    • Dynamic gating transitions not captured by crystallography
  9. 2013 High

    The GIRK2–Gβγ co-crystal structure revealed four Gβγ subunits binding at subunit interfaces, inducing a pre-open intermediate, which explained membrane-delimited activation and burst kinetics.

    Evidence X-ray crystallography of GIRK2–Gβγ complex at 3.5 Å

    PMID:23739333

    Open questions at the time
    • PIP2 was absent from the complex; the fully open Gβγ+PIP2-bound state was not captured
    • Whether four Gβγ are always needed in native channels not established
  10. 2014 High

    Reconstitution of purified GIRK2 in planar bilayers proved that Gβγ AND PIP2 are both required for activation with no additional cellular components, and that Na+ modulates but is not essential, settling long-standing debates about minimal activation requirements.

    Evidence Purified protein reconstituted in planar lipid bilayers; electrophysiology with defined lipid and protein components

    PMID:25049222

    Open questions at the time
    • Heteromeric channels not reconstituted
    • Lipid composition effects beyond PIP2 not systematically tested
  11. 2016 High

    Quantitative analysis showed four Gβγ subunits bind cooperatively and Na+ amplifies opening by increasing Gβγ affinity, establishing the molecular logic by which GIRK2 channels amplify inhibition during elevated neuronal activity.

    Evidence Quantitative activity assay with membrane-anchored G proteins; dopamine neuron patch-clamp

    PMID:27074662

    Open questions at the time
    • Whether cooperativity differs in heteromeric channels unknown
    • In vivo Na+ concentration dynamics during firing not measured
  12. 2012 High

    KCNJ6 trisomy caused hippocampal learning deficits and accentuated long-term depression, directly linking GIRK2 gene dosage to synaptic plasticity impairment relevant to Down syndrome.

    Evidence Behavioral testing and hippocampal slice LTP/LTD electrophysiology in Kcnj6 triploid mice

    PMID:22308328

    Open questions at the time
    • Whether plasticity defects are cell-autonomous or circuit-level was unclear
    • Specific GIRK2-containing channel subtypes responsible not identified
  13. 2016 High

    Genetic normalization of Kcnj6 copy number in the Ts65Dn Down syndrome model rescued GABAB-coupled GIRK currents and infantile spasms, establishing GIRK2 overexpression as necessary for this epileptic phenotype.

    Evidence Genetic Kcnj6 copy-number reduction; GABAB agonist challenge; EEG; patch-clamp; tertiapin-Q pharmacology

    PMID:27462820

    Open questions at the time
    • Whether GIRK2 reduction rescues other DS-associated seizure types unknown
    • Cell-type specificity of the rescue not determined
  14. 2017 High

    Normalizing Kcnj6 from 3 to 2 copies rescued long-term memory and dentate gyrus LTP in Ts65Dn mice, and fluoxetine mimicked this rescue pharmacologically, establishing GIRK2 overdose as a tractable therapeutic target for DS cognitive deficits.

    Evidence Genetic cross; novel object recognition; LTP/STP electrophysiology; fluoxetine treatment of hippocampal slices

    PMID:28342823

    Open questions at the time
    • Whether fluoxetine acts directly on GIRK2 or indirectly via serotonin signaling not resolved
    • Long-term behavioral consequences of chronic GIRK2 suppression unknown
  15. 2015 Medium

    Identification of de novo KCNJ6 mutations as the cause of Keppen-Lubinsky syndrome established KCNJ6 as a Mendelian disease gene, connecting pore-region mutations to severe developmental phenotypes.

    Evidence Whole-exome sequencing of three unrelated patients with in silico structural modeling

    PMID:25620207

    Open questions at the time
    • Functional characterization of Keppen-Lubinsky mutations not performed in this study
    • Genotype-phenotype correlation across different pore mutations not established
  16. 2018 High

    Functional characterization of a KCNJ6 L171R mutation causing hyperkinetic movement disorder showed constitutive inward current with loss of K+ selectivity and gain of Ca2+ permeability, extending the channelopathy mechanism beyond the weaver paradigm.

    Evidence Patch-clamp electrophysiology of heterologously expressed mutant channels; pharmacological characterization

    PMID:29852244

    Open questions at the time
    • Whether Ca2+ permeability contributes to neurodegeneration in patients not tested
    • Effect on heteromeric channels in native neurons not assessed
  17. 2021 High

    Cryo-EM structures revealed cholesterol binding pockets in the GIRK2 transmembrane domain that stabilize PIP2 interaction and promote cytoplasmic domain engagement, adding cholesterol as a third lipid regulator of channel gating.

    Evidence Cryo-EM with and without CHS/PIP2; site-directed mutagenesis eliminating cholesterol potentiation

    PMID:34433062

    Open questions at the time
    • Whether cholesterol regulation differs in heteromeric channels unknown
    • Physiological contexts where cholesterol changes regulate native GIRK2 not defined
  18. 2022 High

    iPSC-derived neurons from AUD subjects with KCNJ6 noncoding variants linked reduced GIRK2 expression to elevated neuronal excitability, and showed ethanol restores excitability via GIRK2 induction, providing a cellular mechanism for alcohol use disorder risk.

    Evidence iPSC-derived glutamatergic neurons; scRNA-seq; patch-clamp; GIRK2 overexpression rescue; ethanol exposure

    PMID:36207584

    Open questions at the time
    • Causal regulatory variants not pinpointed
    • Whether the excitability phenotype drives drinking behavior in vivo is untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • A complete structural model of the fully open, Gβγ- and PIP2-bound heteromeric GIRK1/GIRK2 channel in a native lipid environment is lacking, and the mechanisms governing isoform-specific subcellular trafficking and compartment-dependent coupling to receptors remain unresolved.
  • No structure of an open heteromeric GIRK1/GIRK2 channel with Gβγ and PIP2
  • Trafficking signals directing splice variants to specific dendritic compartments undefined
  • Structural basis for cholesterol-PIP2 cooperativity in heteromeric channels not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0098772 molecular function regulator activity 2
Localization
GO:0005886 plasma membrane 3 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 5 R-HSA-162582 Signal Transduction 4
Partners
DLG4GABBR1GNB1GNG2KCNJ3KCNJ9RGS4
Complex memberships
GIRK1/GIRK2 heterotetramerGIRK2 homotetramerGIRK2/GIRK3 heterotetramer

Evidence

Reading pass · 34 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2011 Crystal structure of mammalian GIRK2 (Kir3.2) revealed a G loop gate in the cytoplasmic domain and an inner helix gate; G proteins open only the G loop gate in the absence of PIP2, but in the presence of PIP2 both gates become coupled and open together. A Na+ ion-binding site was identified that allows intracellular Na+ to modulate channel activity. X-ray crystallography of wild-type and constitutively active mutant GIRK2, with and without PIP2 Cell High 21962516
2013 Crystal structure of mammalian GIRK2 in complex with Gβγ subunits at 3.5 Å resolution showed four Gβγ subunits binding at interfaces between channel subunits via short-range atomic and long-range electrostatic interactions, inducing a pre-open state intermediate between closed and open conformations. The structure supports membrane-delimited activation and explains burst kinetics of gating. X-ray crystallography of GIRK2–Gβγ complex Nature High 23739333
2014 Purified mammalian GIRK2 reconstituted in planar lipid membranes requires simultaneous presence of Gβγ AND PIP2 for activation; Na+ modulates Gβγ/PIP2 effects over physiological concentrations but is not essential; Gαi1(GTPγS) has no effect, while Gαi1(GDP) closes the channel by removing Gβγ. GIRK2 opens as a function of PIP2 mole fraction with Hill coefficient 2.5. Reconstitution in planar lipid bilayers; purified protein; electrophysiology eLife High 25049222
2016 Four Gβγ subunits bind cooperatively to open GIRK2; intracellular Na+ amplifies opening primarily by increasing Gβγ affinity; this dual Gβγ/Na+ responsiveness allows GIRK2 to mediate amplifiable neuronal inhibition during excess electrical activity. Quantitative activity assay with membrane-anchored G proteins; dopamine neuron patch-clamp; reconstituted system eLife High 27074662
2021 Cryo-EM structures of GIRK2 with and without cholesterol analog CHS and PIP2 revealed that CHS binds in lipid-facing hydrophobic pockets of the transmembrane domain near PIP2, stabilizes PIP2 interaction, and promotes engagement of the cytoplasmic domain onto the transmembrane region. Mutagenesis of a CHS binding pocket eliminates cholesterol-dependent potentiation. Cryo-EM structural determination; site-directed mutagenesis; functional assays Cell Reports High 34433062
2019 Molecular dynamics simulations using the GIRK2 crystal structure showed that Na+ ions control the cytosolic gate through an anti-clockwise rotation, whereas Gβγ stabilizes the transmembrane gate in the open state through a rocking movement of the cytoplasmic domain; both effects alter channel interaction with PIP2. All-atom microsecond-scale molecular dynamics simulations based on crystal structure Journal of Biological Chemistry Medium 31659119
2020 Native mass spectrometry and fluorescent lipid binding assays showed PIP2 (PIP4,5P2) binds GIRK2 cooperatively with Hill coefficient ~2.7. Point mutations of specific Kir3.2 residues (K64, R92, K194) distinctly alter PIP isoform selectivity, demonstrating residue-specific contributions to phosphoinositide binding. Native mass spectrometry; fluorescent lipid binding assays; site-directed mutagenesis Biochemistry High 32372643
2003 Gβγ-binding sites were mapped in GIRK2: the N terminus and a C-terminal segment (~residues 320–409) both bind Gβγ. Mutation of C-terminal leucines L273 and L344 in GIRK2 (corresponding to L262/L333 in GIRK1) dramatically altered K+ current properties without reducing Gβγ binding, indicating these residues are important for Gβγ-induced gating changes rather than binding per se. Pulldown/direct binding of Gβγ to GIRK2 fragments; competition assays; Xenopus oocyte electrophysiology with mutant channels Journal of Biological Chemistry High 12743112
2009 Gαi3-GDP (inactive form) regulates GIRK1/GIRK2 heteromeric channels but not homomeric GIRK2; Gαi3-GDP forms heterotrimers with Gβγ that reduce basal activity and increase Gβγ-evoked currents via GIRK1 subunit specifically. In vitro binding showed Gβγ enhanced Gαi3GDP binding to cytosolic domain of GIRK1 but not GIRK2, demonstrating divergent subunit-specific regulation. Xenopus oocyte electrophysiology; in vitro protein binding assays; chimeric/mutant channels Journal of Physiology High 19470775
1996 GIRK2 and GIRK1 co-immunoprecipitate from rat and mouse brain regions where both are expressed (cerebral cortex, hippocampus, cerebellum), demonstrating they form heteromeric channels in vivo. In weaver mice, GIRK2 expression is severely reduced and co-expressed GIRK1 expression is also disrupted, consistent with their co-assembly. Co-immunoprecipitation from brain tissue; immunocytochemistry Journal of Neuroscience High 8929423
1996 The weaver GIRK2 G156S mutation (in the pore-forming H5 region) leads to constitutive activation, loss of K+ selectivity (gain of Na+ permeability), and increased sensitivity to channel blockers when expressed in Xenopus oocytes. Pharmacological blockade of Na+ influx in weaver granule cells restored their ability to differentiate, establishing that Na+ flux through the mutant channel causes the granule cell developmental failure. Xenopus oocyte electrophysiology; pharmacological rescue in primary cerebellar granule cell culture Neuron High 8630252
1996 Expression of weaver mutant GIRK2 (G156S) in Xenopus oocytes results in loss of K+ selectivity: the channel becomes permeable to Na+, causing depolarization. Co-expression with GIRK1 did not prevent this increased Na+ permeability. Xenopus oocyte electrophysiology; ion substitution experiments FEBS Letters High 8706831
1997 GIRK2 knockout mice lack G-protein-activated inwardly rectifying K+ currents in cerebellar granule cells; activation of GABAB receptors fails to induce inwardly rectifying K+ current in GIRK2-null granule cells. GIRK1 expression is also severely reduced in GIRK2-null brain, suggesting GABAB receptors couple to heteromultimers of GIRK1 and GIRK2. Patch-clamp electrophysiology on cerebellar granule cells from knockout mice; pertussis toxin treatment; Ba2+ inhibition PNAS High 9342388
1999 GIRK channels in substantia nigra dopaminergic neurons are composed exclusively of Kir3.2 (GIRK2) subunits (homotetramers of Kir3.2a and Kir3.2c splice variants) without significant Kir3.1 or Kir3.3. Kir3.2c (but not Kir3.2a) binds the PDZ domain-containing protein PSD-95, contributing to localization at postsynaptic membranes of dopaminergic neuron dendrites. Immunoprecipitation from SN tissue; immunolocalization; heterologous expression in oocytes; G-protein stimulation assays Journal of Neuroscience High 9920664
2002 G-protein-gated K+ channels containing Kir3.2 (GIRK2) subunits mediate the acute opioid hyperpolarization of locus coeruleus neurons; Kir3.2 knockout reduced [Met5]enkephalin-induced hyperpolarization by ~40% and Kir3.2/3.3 double knockout reduced it by ~80%, demonstrating that opioid inhibition of LC neurons is primarily mediated by G-protein-gated K+ channels, not cAMP-dependent conductance. Brain slice patch-clamp electrophysiology in Kir3.2 and Kir3.2/3.3 double knockout mice Journal of Neuroscience High 12040038
2000 GIRK2 and GIRK3 co-assemble to form functional heteromultimeric G-protein-gated K+ channels in brain. GIRK2/GIRK3 complexes show ~5-fold lower sensitivity to activation by Gβγ compared to GIRK1/GIRKx channels. GIRK2/GIRK3 complexes were immunoprecipitated from transfected cells and purified from native brain tissue. Co-immunoprecipitation from transfected CHO-K1 cells and native brain; patch-clamp electrophysiology; single-channel analysis Journal of Biological Chemistry High 10956667
2004 GIRK1 and GIRK2 subunits physically interact in spinal cord dorsal horn; lack of either subunit reduces expression of the other, suggesting mutual stabilization through co-assembly. GIRK1 and GIRK2 knockout mice both exhibit hyperalgesia, and spinal administration of the GIRK channel blocker tertiapin produces similar effects, establishing that spinal GIRK1/GIRK2 complexes modulate thermal nociception and contribute to morphine analgesia. Immunohistochemistry; Western blot; behavioral phenotyping of knockout mice; intrathecal drug administration with tertiapin Journal of Neuroscience High 15028774
2002 GIRK2-null mice show markedly reduced or absent antinociception from ethanol, oxotremorine, nicotine, baclofen, clonidine, and cannabinoid receptor agonist WIN 55,212, but not ketamine, establishing that multiple inhibitory GPCR systems (opioid, α-adrenergic, muscarinic, GABAB, cannabinoid) converge on postsynaptic GIRK2 channels for analgesic action. Hot-plate behavioral testing in GIRK2-null mice; pharmacological challenge with multiple receptor agonists PNAS High 12493843
2002 GIRK2 deletion selectively reduced clonidine antinociception (almost completely) and significantly reduced morphine antinociception in spinal reflex tests. GIRK2-null mutation eliminated sex differences in pain threshold, revealing that GIRK2-coupled postsynaptic receptors mediate basal sex differences in pain sensitivity and that α2-adrenergic analgesia is primarily postsynaptic. Spinal reflex behavioral testing in GIRK2-null mice of both sexes; morphine and clonidine dose-response PNAS High 12496346
2013 GIRK channels are absent from mouse peripheral sensory neurons but present in human and rat. Transgenic expression of GIRK channels in mouse nociceptors established peripheral opioid signaling and local analgesia, demonstrating GIRK2 is both necessary and sufficient for peripheral opioid analgesia. A regulatory element in the rat GIRK2 gene accounts for differential expression in rodents. Immunostaining; transgenic mouse expression; behavioral pain assays; gene regulatory element analysis EMBO Molecular Medicine High 23818182
2006 Kir3.2 (GIRK2) subunit immunoreactivity is localized postsynaptically to extrasynaptic plasma membrane of dendritic shafts and spines of hippocampal pyramidal cells. On dendritic spines, Kir3.2 and GABAB1 show high degree of co-clustering around excitatory synapses (via SDS-digested freeze-fracture replica immunolabeling), whereas in dendritic shafts they are mainly segregated, suggesting compartment-dependent functional coupling. High-resolution immunocytochemistry; freeze-fracture replica immunolabeling; quantitative immunogold analysis Journal of Neuroscience High 16624949
2012 BRET and co-immunoprecipitation studies showed that δ-opioid receptors, Gβγ, and Kir3 subunits constitutively interact. DOR activation produces conformational changes at Gβγ-Kir3.1 interface with kinetics and efficacy order matching those at DOR-Gβγ and GαoA-Gβγ interfaces; these changes were lost when Kir3.1 lacked Gβγ-activation sites, establishing that agonist-encoded conformational information is relayed to the channel via Gβγ repositioning. BRET between signaling partners; co-immunoprecipitation; pertussis toxin treatment; mutagenesis of Gβγ-binding sites Molecular Pharmacology High 23175530
2000 RGS4 co-expression in Xenopus oocytes accelerates GIRK1/GIRK2 deactivation kinetics after kappa-opioid receptor activation, reduces basal channel activity, and abolishes post-stimulation reduction of basal conductance. This demonstrates that RGS4 (GTPase-activating protein) modulates GIRK2-containing channel gating by accelerating GTP hydrolysis on Gα. Xenopus oocyte electrophysiology; co-expression of RGS4 with GIRK1/GIRK2 and kappa-opioid receptor Life Sciences Medium 11065178
1996 A novel GIRK2 isoform, GIRK2B (shorter C-terminus), enhances GIRK1-mediated G-protein-gated K+ current when co-expressed in Xenopus oocytes, demonstrating it can form functional heteromultimeric channels with GIRK1. Xenopus oocyte electrophysiology; RT-PCR tissue distribution Biochemical and Biophysical Research Communications Medium 8573147
1999 Kir3.2d, a novel testis-specific splice variant of GIRK2 lacking 18 N-terminal amino acids, forms functional homomultimeric G-protein-gated K+ channels when expressed alone in oocytes or HEK293T cells. Kir3.2d immunoreactivity is localized exclusively in acrosomal vesicles of spermatids in mouse testis, suggesting a role in acrosome development during spermiogenesis. cDNA library screening; heterologous expression in Xenopus oocytes and HEK293T; electrophysiology; immunolocalization Journal of Physiology Medium 10562331
2015 De novo heterozygous mutations in KCNJ6 (p.Thr152del and p.Gly154Ser) cause Keppen-Lubinsky syndrome, establishing KCNJ6 as a channelopathy gene. The mutations are in the pore/channel region consistent with severely impaired K+ channel function. Whole-exome sequencing of three unrelated patients; in silico modeling consistent with channel dysfunction American Journal of Human Genetics Medium 25620207
2018 A de novo KCNJ6 mutation (p.Leu171Arg) in a patient with hyperkinetic movement disorder produces an aberrant constitutive inward current lacking G-protein activation, with loss of K+ selectivity and gain of Ca2+ permeability when expressed heterologously. Expression of a GIRK1-GIRK2(L171R) tandem dimer produced no current, suggesting heterotetramers are non-functional. The current was inhibited by Na+ channel blocker QX-314, similar to the weaver mutation. Whole-exome sequencing; heterologous expression in cells; patch-clamp electrophysiology; pharmacological characterization Neuroscience High 29852244
2017 GIRK2a and GIRK2c splice isoforms show distinct subcellular distribution in hippocampal pyramidal neurons: GIRK2c achieves more uniform distribution and supports inhibitory postsynaptic currents in distal dendrites better than GIRK2a. Over-expression of GIRK2a (but not GIRK2c) in dorsal CA1 also enhanced cue fear learning, demonstrating isoform-specific functional consequences. Viral expression in Girk2-/- hippocampal neurons; patch-clamp electrophysiology; contextual and cue fear conditioning behavioral assays Scientific Reports Medium 28487514
2012 Genetic trisomy of Kcnj6 (GIRK2) in mice causes deficits in hippocampal-dependent learning and memory, altered reward responses, hampered depotentiation, and accentuated long-term synaptic depression, demonstrating that increased GIRK2 gene dose directly impairs synaptic plasticity and cognitive function. Behavioral tests (Morris water maze, reward); LTP/LTD electrophysiology in hippocampal slices from Kcnj6 triploid mice PNAS High 22308328
2017 Reducing Kcnj6 gene copy number from 3 to 2 in Ts65Dn Down syndrome model mice restored hippocampal Kir3.2 protein to normal levels and rescued both long-term memory and short-term/long-term potentiation in dentate gyrus. Fluoxetine (a GIRK2 channel suppressor) also rescued synaptic plasticity in Ts65Dn dentate gyrus slices, demonstrating that increased KCNJ6 dose is necessary for synaptic and cognitive dysfunction in this DS model. Genetic cross to reduce Kcnj6 copy number; novel object recognition memory test; LTP/STP electrophysiology in dentate gyrus slices; pharmacological rescue with fluoxetine Neurobiology of Disease High 28342823
2016 Reduction of Kcnj6 copy number in Ts65Dn mice rescued GABAB receptor agonist-induced infantile spasms phenotype, and GABAB-mediated GIRK2 currents were increased in trisomic hippocampal neurons and normalized in disomic mice. Pharmacological blockade with tertiapin-Q also rescued the phenotype, demonstrating GABAB-coupled GIRK2 channels are necessary for the infantile spasms phenotype in this DS model. Genetic Kcnj6 knockdown; GABAB agonist treatment; EEG monitoring; patch-clamp of hippocampal neurons; tertiapin-Q pharmacology Annals of Neurology High 27462820
1999 Co-expression of GIRK1 with weaver GIRK2(G156S) in Xenopus oocytes rescues K+ selectivity and G-protein dependence: linked tetramers with GIRK1 and GIRK2wv in alternating array give wild-type K+ selective currents, while adjacent mutant subunits produce weaver-like currents. This demonstrates that GIRK1 subunit position within the tetramer determines channel selectivity. Xenopus oocyte electrophysiology; linked dimer and tetramer constructs with defined subunit arrangements Journal of Neuroscience High 10493734
2008 Transgenic mice carrying human KCNJ6 show increased Kir3.2 expression in atria and enhanced chronotropic responses to muscarinic (carbachol, methoxamine) and adenosine (CCPA) stimulation, demonstrating that KCNJ6/GIRK2 overexpression alters sino-atrial and atrial G-protein-coupled K+ channel function and heart rate regulation. Transgenic mouse model; ECG recordings under drug challenge; RT-PCR and Western blot quantification Physiological Genomics Medium 18303085
2022 iPSC-derived glutamatergic neurons from AUD subjects with KCNJ6 noncoding variants express lower GIRK2, have greater neurite area, and elevated excitability. Ethanol exposure induces GIRK2 expression and reverses the elevated excitability. Ectopic GIRK2 overexpression alone mimics the effect of ethanol in normalizing excitability, establishing that KCNJ6 variants decrease GIRK2 expression, increase neuronal excitability, and that ethanol acts via GIRK2 induction. iPSC-derived neurons; single-cell RNA sequencing; patch-clamp electrophysiology; GIRK2 overexpression; ethanol treatment Molecular Psychiatry High 36207584

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2011 Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium. Cell 366 21962516
1997 Normal cerebellar development but susceptibility to seizures in mice lacking G protein-coupled, inwardly rectifying K+ channel GIRK2. Proceedings of the National Academy of Sciences of the United States of America 291 9023358
2013 X-ray structure of the mammalian GIRK2-βγ G-protein complex. Nature 258 23739333
2007 XIAP induces NF-kappaB activation via the BIR1/TAB1 interaction and BIR1 dimerization. Molecular cell 232 17560374
2000 The survivin-like C. elegans BIR-1 protein acts with the Aurora-like kinase AIR-2 to affect chromosomes and the spindle midzone. Molecular cell 217 10983970
1996 Heteromultimerization of G-protein-gated inwardly rectifying K+ channel proteins GIRK1 and GIRK2 and their altered expression in weaver brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 214 8929423
2013 Arabidopsis receptor-like protein30 and receptor-like kinase suppressor of BIR1-1/EVERSHED mediate innate immunity to necrotrophic fungi. The Plant cell 206 24104566
1999 Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis. Current biology : CB 204 10209096
1996 Functional analysis of the weaver mutant GIRK2 K+ channel and rescue of weaver granule cells. Neuron 171 8630252
1999 Characterization of G-protein-gated K+ channels composed of Kir3.2 subunits in dopaminergic neurons of the substantia nigra. The Journal of neuroscience : the official journal of the Society for Neuroscience 170 9920664
2002 Contribution of GIRK2-mediated postsynaptic signaling to opiate and alpha 2-adrenergic analgesia and analgesic sex differences. Proceedings of the National Academy of Sciences of the United States of America 168 12496346
2002 G-protein-gated potassium channels containing Kir3.2 and Kir3.3 subunits mediate the acute inhibitory effects of opioids on locus ceruleus neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 163 12040038
2002 A pervasive mechanism for analgesia: activation of GIRK2 channels. Proceedings of the National Academy of Sciences of the United States of America 124 12493843
2006 Compartment-dependent colocalization of Kir3.2-containing K+ channels and GABAB receptors in hippocampal pyramidal cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 120 16624949
2004 Spinal G-protein-gated K+ channels formed by GIRK1 and GIRK2 subunits modulate thermal nociception and contribute to morphine analgesia. The Journal of neuroscience : the official journal of the Society for Neuroscience 116 15028774
2014 Quantitative analysis of mammalian GIRK2 channel regulation by G proteins, the signaling lipid PIP2 and Na+ in a reconstituted system. eLife 108 25049222
2006 A Bir1-Sli15 complex connects centromeres to microtubules and is required to sense kinetochore tension. Cell 103 17174893
2001 Potassium channels as targets for ethanol: studies of G-protein-coupled inwardly rectifying potassium channel 2 (GIRK2) null mutant mice. The Journal of pharmacology and experimental therapeutics 98 11454913
1997 Defective gamma-aminobutyric acid type B receptor-activated inwardly rectifying K+ currents in cerebellar granule cells isolated from weaver and Girk2 null mutant mice. Proceedings of the National Academy of Sciences of the United States of America 96 9342388
1996 The weaver mutation of GIRK2 results in a loss of inwardly rectifying K+ current in cerebellar granule cells. Proceedings of the National Academy of Sciences of the United States of America 96 8855331
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