Affinage

KCNJ3

G protein-activated inward rectifier potassium channel 1 · UniProt P48549

Length
501 aa
Mass
56.6 kDa
Annotated
2026-06-10
100 papers in source corpus 44 papers cited in narrative 43 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

KCNJ3 (GIRK1/Kir3.1) encodes an inwardly rectifying K+ channel subunit that transduces Gi/o-coupled GPCR signaling into membrane hyperpolarization, mediating parasympathetic control of heart rate and neuronal inhibition (PMID:12374786, PMID:15028774). GIRK1 does not form functional homomers; it requires obligatory hetero-assembly with a partner Kir3 subunit (Kir3.4/GIRK4 in heart, GIRK2 in brain) both for plasma membrane targeting and for channel function, and co-assembly reciprocally stabilizes subunit expression (PMID:8929423, PMID:8789957, PMID:8938714). Channel activation proceeds by direct binding of Gβγ — liberated upon receptor-triggered Gαi/Gβγ dissociation — to both the N-terminal and C-terminal cytoplasmic domains, with four Gβγ molecules engaging an intersubunit cleft spanning adjacent subunits to drive conformational rearrangements that open the cytoplasmic G-loop gate (PMID:7576656, PMID:7626088, PMID:21075842, PMID:23943609). Crystallographic and chimeric analyses localize the gating machinery to the long acidic cytoplasmic pore that creates the polyamine-block environment underlying inward rectification, the G-loop apex and inner helix bundle gates, and the selectivity filter, which itself acts as an agonist-activated gate; a conserved salt bridge behind the filter maintains K+ selectivity and rectification, and PIP2 binding is required for gating (PMID:12507423, PMID:17703190, PMID:15723059, PMID:14504281). The unique distal C-terminus of GIRK1 confers the channel's hallmark high basal activity by recruiting Gβγ to the membrane and by enhancing GαiGDP binding, distinguishing GIRK1-containing channels from GIRK2/GIRK4 homomers (PMID:19470775, PMID:25384780). Channel output is further tuned by PKA phosphorylation (an off/on switch via PP2A-reversible facilitation), PKCδ-mediated inhibition downstream of Gq-coupled receptors, and assembly within native signaling complexes containing G proteins, kinases, phosphatases, and scaffolds (PMID:15037627, PMID:12547819, PMID:15857907, PMID:23305758). Physiologically, the cardiac GIRK1/4 IKACh channel slows heart rate, and a gain-of-function p.N83H mutation that elevates basal IKACh causes bradyarrhythmia (PMID:12374786, PMID:30764634); brain GIRK1-containing channels localize postsynaptically and are required for opioid analgesia, nociception, synaptic plasticity, and spatial memory (PMID:15028774, PMID:8604043, PMID:9023373, PMID:33124684).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Established the core activation mechanism — whether GPCR signaling reaches the channel directly — by showing released Gβγ physically binds GIRK1 cytoplasmic domains to gate it.

    Evidence GST pull-downs with purified G protein subunits, synthetic peptide competition, and domain-swap chimeras with electrophysiology in Xenopus oocytes

    PMID:7576656 PMID:7576657 PMID:7626088

    Open questions at the time
    • Stoichiometry and structural nature of the Gβγ–channel interface unresolved
    • Did not distinguish binding from gating-competent conformational change
  2. 1996 High

    Resolved why GIRK1 alone is non-functional, establishing obligatory hetero-assembly for both trafficking and channel activity.

    Evidence Co-IP from native brain and COS cells, antisense knockdown of endogenous partner in oocytes, immunofluorescence localization, and weaver mouse analysis

    PMID:8789957 PMID:8929423 PMID:8938714

    Open questions at the time
    • Subunit stoichiometry of native heterotetramers not yet defined
    • Tissue-specific partner identity (GIRK2 vs GIRK4) inferred from co-expression
  3. 2002 High

    Provided atomic-level structural basis for inward rectification by showing the long acidic cytoplasmic pore creates a favorable environment for polyamine block.

    Evidence 1.8 Å crystal structure of the GIRK1 cytoplasmic N/C-terminal domains

    PMID:12507423

    Open questions at the time
    • Structure of cytoplasmic domain only, not the intact membrane channel
    • Did not capture Gβγ-bound or open states
  4. 2005 High

    Identified the G-loop as a discrete cytoplasmic gate separating the cytoplasmic and transmembrane pores.

    Evidence Crystal structure of the Kir3.1 cytoplasmic domain plus site-directed mutagenesis disrupting gating/rectification

    PMID:15723059

    Open questions at the time
    • Coupling of G-loop motion to Gβγ binding not yet structurally captured
  5. 2007 High

    Defined the transmembrane gating architecture, demonstrating a KcsA-identical selectivity filter, two constriction gates, and PIP2-interacting residues.

    Evidence Two crystal structures (open and closed) of a Kir3.1–KirBac1.3 chimera at 2.2 Å

    PMID:17703190

    Open questions at the time
    • Chimera transmembrane region is prokaryotic, not native GIRK1
    • How Gβγ binding propagates to the filter not resolved
  6. 2009 High

    Explained the unique high basal activity of GIRK1-containing channels by attributing it to the distal C-terminus enhancing GαiGDP binding.

    Evidence Electrophysiology, in vitro binding assays, and chimeric channel constructs in Xenopus oocytes

    PMID:19470775

    Open questions at the time
    • Structural basis of the distal C-terminal GαiGDP interaction unknown
    • Physiological consequence of high basal activity in native tissue not addressed here
  7. 2010 High

    Quantified the Gβγ–channel stoichiometry and interface, showing four Gβγ bind a tetramer at an intersubunit site driving conformational change.

    Evidence ITC and NMR chemical-shift mapping on purified GIRK1 cytoplasmic pore

    PMID:21075842

    Open questions at the time
    • Weak affinity (~250 µM) measured on isolated domain, not full channel in membrane
    • Open-state structure not captured
  8. 2013 High

    Validated a molecular model of how Gβγ opens the gate, identifying the intersubunit LM/DE-loop cleft and demonstrating gating residues distinct from binding residues.

    Evidence Computational docking with reciprocal rescue mutagenesis and disulfide cross-linking yielding constitutive activation; oocyte electrophysiology

    PMID:12743112 PMID:23943609

    Open questions at the time
    • Model derived from docking, not a co-structure
    • Conformational pathway from cleft to G-loop inferred
  9. 2016 High

    Clarified subunit-specific signal integration by showing GIRK1 mimics a Na+-occupied GIRK4 subunit, rendering GIRK1/4 channels constitutively Gβγ-responsive.

    Evidence Purified protein reconstitution in lipid bilayers with defined ligands

    PMID:27074664

    Open questions at the time
    • Structural basis of the Na+-mimicry not defined
    • Brain GIRK1/2 channel Na+ handling not addressed
  10. 2004 High

    Established the in vivo physiological roles of GIRK1 channels in cardiac IKACh and spinal opioid analgesia.

    Evidence Knockout mice with native atrial patch-clamp and behavioral pain testing plus tertiapin blockade

    PMID:12374786 PMID:15028774

    Open questions at the time
    • Cellular circuits underlying analgesia phenotype not fully dissected
    • Mild tachycardia phenotype indicates partial compensation
  11. 2013 Medium

    Characterized post-translational tuning of channel activity through PKA phosphorylation and PKCδ inhibition acting on defined residues and within native signaling complexes.

    Evidence Single-channel recordings with defined enzymes, PKA/PKC site mutagenesis, dominant-negative PKCδ, confocal imaging, and co-IP from native atrial tissue

    PMID:12547819 PMID:15037627 PMID:15857907 PMID:23305758

    Open questions at the time
    • Crosstalk between kinase modulation and Gβγ gating not integrated structurally
    • Mostly heterologous or single-lab systems
  12. 2014 High

    Defined a 'Gβγ recruitment' mechanism by which the GIRK1 distal C-terminus concentrates membrane Gβγ to elevate basal current independent of the activation mechanism.

    Evidence Fluorescence/BRET assays, binding assays, and truncation/chimeric mutants with electrophysiology in oocytes

    PMID:16787947 PMID:25384780

    Open questions at the time
    • Whether recruitment operates in native neurons/cardiomyocytes not tested
    • Relationship to pre-assembled receptor–G protein–channel complexes not fully resolved
  13. 2020 Medium

    Established GIRK1's requirement for synaptic plasticity and memory and demonstrated subtype-selective pharmacological control plus a disease-causing cardiac mutation.

    Evidence Knockout/knockin mice with behavioral and LTP assays; subtype-selective small molecule (GAT1508) with mutagenesis-validated site; p.N83H variant in heterologous cells and transgenic zebrafish

    PMID:30764634 PMID:31953327 PMID:33124684

    Open questions at the time
    • Mechanistic link from channel activity to depotentiation/memory circuits incomplete
    • Single-lab models for each finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of an intact, native mammalian GIRK1-containing heterotetramer captured in Gβγ-bound open and closed states, integrating PIP2, polyamine, and kinase modulation, remains to be determined.
  • No full-length native heterotetramer structure
  • Conformational coupling from intersubunit Gβγ cleft to selectivity-filter gate not directly observed
  • Subunit-specific gating differences between cardiac GIRK1/4 and neuronal GIRK1/2 not structurally explained

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0060089 molecular transducer activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 3 GO:0005856 cytoskeleton 1
Pathway
R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3 R-HSA-397014 Muscle contraction 2
Partners
GABBR1GNAI3GNB1GNG2KCNJ5KCNJ6KCNJ9OPRD1
Complex memberships
GIRK1/GIRK2 heterotetramerGIRK1/GIRK3 heterotetramerGIRK1/GIRK4 (IKACh) heterotetramer

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Crystal structure of the cytoplasmic pore of GIRK1 (intracellular N- and C-termini) at 1.8 Å resolution revealed a cytoplasmic pore ~60 Å long lined by acidic and hydrophobic amino acids, explaining inward rectification by providing a favorable environment for polyamine block and implicating this domain in G protein regulation. X-ray crystallography (1.8 Å resolution) Cell High 12507423
2007 Crystal structure of a Kir3.1-prokaryotic KirBac1.3 chimera at 2.2 Å revealed that the selectivity filter is structurally identical to KcsA, multiple K+ ions reside in the pore, and two constrictions (inner helix bundle crossing and cytoplasmic pore apex) function as gates; gating of the apex involves rigid-body movements of cytoplasmic pore subunits. Phosphatidylinositol 4,5-bisphosphate (PIP2)-interacting residues were identified, suggesting a mechanism for lipid regulation of the cytoplasmic gate. X-ray crystallography (2.2 Å, two structures in open and closed conformations) The EMBO journal High 17703190
2005 Crystal structure of the cytoplasmic domain of Kir3.1 (Kir3.1S) in the absence of PIP2 showed the cytoplasmic ion-permeation pathway occluded by four cytoplasmic loops (G-loop) forming a girdle around the pore; G-loop mutations disrupted gating or inward rectification, identifying the G-loop as a diffusion barrier / gate between cytoplasmic and transmembrane pores. X-ray crystallography plus functional validation by site-directed mutagenesis Nature neuroscience High 15723059
1995 Gβγ directly binds to both the N-terminal hydrophilic domain and amino acids 273–462 of the C-terminal domain of GIRK1; synthetic peptides from either domain reduced Gβγ binding and Gβγ activation of the channel, establishing direct physical coupling as the mechanism of channel activation. Direct binding assays (pull-down), synthetic peptide competition, electrophysiology in Xenopus oocytes Neuron High 7576656
1995 The N-terminal and part of the C-terminal hydrophilic domain of GIRK1 are required for G protein (Gβγ) gating; chimeras replacing these domains with corresponding regions from the G-protein-insensitive IRK1 abolished Gβγ sensitivity, while the hydrophobic M1-H5-M2 core determines single-channel open time kinetics but not Gβγ sensitivity. Chimera construction and electrophysiology (two-electrode voltage clamp in Xenopus oocytes) Neuron High 7576657
1995 Gβγ directly binds to the C-terminus of GIRK1; Gβγ dissociated from Gα-GTP binds the GST-fused C-terminus, and Gα-GDP (but not Gα-GTPγS) inhibits this binding, demonstrating that receptor-triggered Gα/Gβγ dissociation releases Gβγ to activate GIRK1. GST pull-down with purified G protein subunits Biochemical and biophysical research communications High 7626088
1996 GIRK1 and GIRK2 co-immunoprecipitate from brain regions where both are expressed (cerebral cortex, hippocampus, cerebellum), demonstrating that they form heteromeric channels in vivo; loss of GIRK2 in weaver mice also reduces GIRK1 expression in co-expressing regions, indicating co-assembly-dependent stabilization. Co-immunoprecipitation from native brain tissue; immunohistochemistry The Journal of neuroscience High 8929423
1996 GIRK1 requires a partner subunit (endogenous Xenopus XIR / CIR) to form functional channels; antisense knockdown of endogenous XIR reduced m2-receptor-evoked GIRK1 currents by 80%, demonstrating GIRK1 does not form functional homomeric channels in vivo. Antisense oligonucleotide knockdown of endogenous XIR in Xenopus oocytes; two-electrode voltage clamp Neuron High 8789957
2002 Kir3.1 knockout mice lose carbachol-induced IKACh in atrial myocytes; only low-level, quickly running-down Kir3.4-like activity remained (in 40% of patches), demonstrating that Kir3.1 confers properties enhancing IKACh activity and that Kir3.4 homomultimers do not significantly contribute to native IKACh. Both Kir3.1 and Kir3.4 knockout mice showed mild resting tachycardia. Knockout mouse; patch-clamp electrophysiology in native atrial myocytes The Journal of biological chemistry High 12374786
2003 Gβγ-binding sites in GIRK1 include the N-terminus and two C-terminal segments; a unique Gβγ-interacting segment in the first half of the C-terminus is present in GIRK1 but absent in GIRK2. Mutation of C-terminal leucines L262 and L333 dramatically altered gating properties without reducing Gβγ binding, indicating these residues are important for Gβγ-induced gating changes rather than binding per se. Pull-down binding assays with GST-fused fragments; site-directed mutagenesis; electrophysiology in Xenopus oocytes The Journal of biological chemistry High 12743112
2004 GIRK1/GIRK2 heteromeric channels in the superficial dorsal horn spinal cord modulate thermal nociception; GIRK1-KO mice exhibited thermal hyperalgesia (tail-flick test) and reduced analgesic response to high-dose intrathecal morphine, establishing a role for spinal GIRK1/2 channels in opioid analgesia. Knockout mice; behavioral pain testing; pharmacological blockade with tertiapin The Journal of neuroscience High 15028774
2004 Atrial KACh channels (GIRK1/GIRK4 heterotetramer) exist in a signaling complex with Gβγ, G protein-coupled receptor kinase, PKA, PP1, PP2A, receptor for activated C kinase 1 (RACK1), and actin; PKC potently inhibits Gβγ-induced GIRK channel activity, validated by single-channel recordings. Co-immunoprecipitation from native atrial tissue; single-channel electrophysiology; pharmacological modulation The Journal of biological chemistry High 15037627
2010 NMR and ITC analyses showed that four Gβγ molecules bind to a tetramer of the GIRK1 cytoplasmic pore with Kd ~250 µM; the Gβγ binding site spans two neighboring subunits, and binding causes inter-subunit conformational rearrangements, suggesting a mechanism for gating. Isothermal titration calorimetry (ITC); NMR spectroscopy (chemical shift perturbation mapping) The Journal of biological chemistry High 21075842
2013 Computational docking of Gβγ onto the GIRK1 cytosolic domain predicted that Gβγ acts at an intersubunit cleft formed by LM and DE loops of adjacent subunits to stabilize the G-loop gate open state; mutagenesis of predicted interacting residues in GIRK1 or Gβγ disrupted activation, and reciprocal rescue mutations restored it; disulfide cross-linking of cysteine mutants at predicted interface yielded constitutively activated channels. Computational protein-protein docking; site-directed mutagenesis; disulfide cross-linking; electrophysiology in Xenopus oocytes Science signaling High 23943609
2016 Using purified proteins and lipid bilayers, GIRK1/4 heterotetramers were found not to be activated by intracellular Na+, in contrast to GIRK4 homotetramers where Na+ binding increases Gβγ affinity. GIRK1/4 heterotetramers display constitutively high Gβγ responsiveness, equivalent to GIRK4 homotetramers with Na+ permanently bound, indicating the GIRK1 subunit mimics a Na+-occupied GIRK4 subunit. Purified protein reconstitution in lipid bilayers; electrophysiology with defined ligands eLife High 27074664
1997 Using homomeric GIRK1(F137S) and GIRK4(S143T) functional mutants, Gβγ was shown to be the primary but not exclusive regulator of both GIRK1 and GIRK4; functionally important G protein interaction sites reside in homologous (not divergent terminal) regions shared between GIRK1 and GIRK4. Site-directed mutagenesis; co-expression with G protein subunits and receptors in Xenopus oocytes; electrophysiology The Journal of biological chemistry High 9395492
2006 BRET and co-immunoprecipitation experiments in living cells showed that heterotrimeric G proteins (Gαs, Gαi, Gβ1, Gγ2) form stable pre-existing complexes with Kir3.1 channel subunits at the plasma membrane and at intracellular sites before membrane delivery; receptor agonist stimulation increased BRET between effector and Gβγ, suggesting conformational rather than purely dissociative changes. Bioluminescence resonance energy transfer (BRET); co-immunoprecipitation in living mammalian cells Journal of cell science High 16787947
2009 GαiGDP (but not GαiGTP) regulates GIRK1-containing channels by forming heterotrimers with Gβγ; this regulation is specific to GIRK1-containing channels and not GIRK2 homotetramers. The unique distal C-terminus of GIRK1 mediates enhanced Gαi3GDP binding and the high basal activity characteristic of GIRK1-containing channels. Electrophysiology in Xenopus oocytes; in vitro protein binding assays; chimeric channel constructs The Journal of physiology High 19470775
2014 The distal C-terminus of GIRK1 (G1-dCT) recruits Gβγ to the plasma membrane (a phenomenon termed 'Gβγ recruitment'), increasing local Gβγ availability and thereby elevating basal channel activity; truncation of G1-dCT reduces Gβγ binding and abolishes Gβγ recruitment and basal current without impairing the activation mechanism itself. Fluorescence/BRET assays in Xenopus oocytes; biochemical binding assays; electrophysiology; truncation and chimeric mutants The Journal of physiology High 25384780
1996 Epitope-tagged GIRK1 localizes to internal cytoskeletal structures (co-staining with vimentin) when expressed alone; plasma membrane targeting of GIRK1 is detectable only upon co-expression with CIR (Kir3.4), and CIR co-immunoprecipitates GIRK1, establishing that hetero-assembly is required for plasma membrane localization of GIRK1. Immunofluorescence localization; co-immunoprecipitation from metabolically labeled COS cells; dominant-negative mutagenesis Neuropharmacology High 8938714
2000 Mutation of a charged glutamate-arginine salt bridge ('bowstring') behind the selectivity filter of Kir3.1/Kir3.4 reduces or abolishes K+ selectivity and polyamine-induced inward rectification; molecular modeling shows the salt bridge maintains rigid pore structure and K+ selectivity. Site-directed mutagenesis; electrophysiology; molecular modeling The Journal of biological chemistry High 14504281
2003 Mutations within the selectivity filter of Kir3.1/Kir3.4 that increased filter flexibility and abolished K+ selectivity also abolished agonist (Gβγ) activation, while mutations that did not affect selectivity had little effect on activation; this identifies the selectivity filter as the agonist-activated gate. Site-directed mutagenesis; electrophysiology The Journal of biological chemistry Medium 14525972
2000 Mutagenesis of negatively charged residues throughout the pore of Kir3.1/Kir3.4 (in H5, M2, and proximal C-terminus) reduced or abolished slow activation; slow activation is principally caused by unbinding of polyamines from negatively charged residues near the selectivity filter, not an intrinsic gating mechanism. Site-directed mutagenesis; inside-out and cell-attached patch clamp; polyamine perfusion experiments The Journal of biological chemistry Medium 10956662
1995 Desensitization of mu opioid receptor-coupled GIRK1 currents occurs downstream of the receptor, likely at the channel itself; the rate of desensitization was unaffected by removal of Ca2+, elevation of cAMP, PKC activators, phosphatase inhibitors, or cytoskeletal disruption, suggesting it does not involve calcium- or phosphorylation-dependent mechanisms. Two-electrode voltage clamp in Xenopus oocytes; pharmacological dissection The Journal of biological chemistry Medium 7822283
2000 PKA phosphorylation facilitates GIRK1/GIRK4 channel activity by increasing open probability and open-time duration; the last 20 C-terminal amino acids of GIRK1 are required for PP2A-mediated dephosphorylation to reduce apparent Gβγ affinity, constituting an off-switch. Single-channel recordings from inside-out patches in Xenopus oocytes; exogenous PKA-cs and PP2A application; C-terminal truncation Biophysical journal Medium 12547819
1997 A synthetic peptide (DS6) derived from the distal C-terminus of GIRK1 directly blocks GIRK channel activity from the cytoplasmic side by reducing burst duration and increasing long closed times; block was not due to competition with Gβγ, implicating the distal C-terminus as part of the intrinsic gate. Inside-out patch-clamp recordings; exogenous peptide application in Xenopus oocytes The Journal of physiology Medium 9409468
2005 PKC-delta specifically mediates Gq-coupled M3 receptor inhibition of Kir3.1/Kir3.2 channels; recombinant PKC-delta applied to inside-out patches inhibited channel activity; M3-mediated inhibition was blocked by dominant-negative PKC-delta constructs; PIP2 depletion alone was insufficient, and PKC-delta translocation to the plasma membrane was confirmed by confocal microscopy. Inside-out patch clamp; dominant-negative constructs; confocal microscopy of GFP-tagged PKC-delta; phosphorylation assays American journal of physiology. Cell physiology Medium 15857907
2013 PKA phosphorylation of GIRK1 (at S385, S401, T407) and GIRK4 (at T199, S412) both contribute to heterologous facilitation of GIRK1/4 channels; channels lacking both sets of PKA sites (GIRK1-S385C/S401C/T407C + GIRK4-T199C/S412C) were essentially devoid of PKA-mediated effects. Site-directed mutagenesis of PKA phosphorylation sites; in vitro phosphorylation assays; electrophysiology in Xenopus oocytes Biochimica et biophysica acta Medium 23305758
2010 The Kir3.1 chimera (Kir3.1 cytoplasmic domain with KirBac1.3 transmembrane pore) reconstituted in planar lipid bilayers functions as a bona fide inward rectifier K+ channel requiring PIP2; channel activity was stimulated by ethanol and required both activated Gα and Gβγ for full gating. Functional reconstitution in planar lipid bilayers; single particle electron microscopy The Journal of biological chemistry Medium 20937804
2010 GABAB receptors form stable oligomeric complexes with GIRK1/GIRK3 heterotetramers; BRET shows direct interaction between GABAB receptor and GIRK1/GIRK3 in living cells; these complexes form shortly after biosynthesis, likely in the ER/Golgi, and were confirmed in vivo in cerebellar granule cells by co-immunoprecipitation and electron microscopy. BRET; co-immunoprecipitation; confocal and electron microscopy The European journal of neuroscience Medium 20846323
2012 BRET and co-immunoprecipitation studies showed that δ-opioid receptors (DORs), Gβγ, and Kir3.1/Kir3.2 subunits constitutively interact; DOR activation modulated BRET at DOR-GαoA, DOR-Gβγ, GαoA-Gβγ, and Gβγ-Kir3.1 interfaces; conformational changes at the Gβγ/Kir3.1 interface predicted ligand ability to evoke channel currents and were lost with Gβγ-binding-deficient Kir3.1 mutants. BRET; co-immunoprecipitation; site-directed mutagenesis; electrophysiology in HEK293 cells Molecular pharmacology Medium 23175530
2012 Three unique P-loop residues in Girk1 (F137, A142, Y150) collectively potentiate both receptor-dependent and receptor-independent heteromeric channel activity by enhancing mean open time and single-channel conductance; residue Q404 in the distal C-terminal domain is a key determinant of receptor-induced activity; residue F162 in the second transmembrane domain tempers the P-loop potentiating influence. Site-directed mutagenesis; single-channel and whole-cell electrophysiology in transfected cells and hippocampal neurons Proceedings of the National Academy of Sciences of the United States of America Medium 23236146
2000 GIRK1 is glycosylated at Asn119; N-glycosylation at this site does not affect physical assembly with GIRK4, plasma membrane targeting of the heteromer, or heteromeric channel function. GIRK1 transmembrane domain 1 is required for efficient glycosylation at Asn119. Site-directed mutagenesis; glycosidase treatment; immunoblotting in Xenopus oocytes The Journal of biological chemistry Medium 10889209
1995 A myristoylated C-terminal tail fragment of GIRK1 (aa 183–501, src+183–501) expressed in Xenopus oocytes strongly inhibits G protein-gated GIRK currents by interfering with functional activation by G proteins, functioning partly as a blocking particle and partly by competing for free Gβγ; the non-myristoylated form had no effect. Dominant-negative expression in Xenopus oocytes; two-electrode voltage clamp; immunological membrane localization assays Proceedings of the National Academy of Sciences of the United States of America Medium 7542774
2019 A gain-of-function KCNJ3 missense mutation (p.N83H) increases basal IKACh current even in absence of muscarinic receptor stimulation; transgenic zebrafish expressing mutant human KCNJ3 developed bradyarrhythmia phenotypes reversible by the selective IKACh blocker NIP-151. Whole-exome sequencing; cellular electrophysiology in heterologous expression; transgenic zebrafish model; pharmacological rescue Circulation Medium 30764634
1997 C-terminal alternative splice variants of Kir3.1 (including truncated Kir3.1(00) lacking the main Gβγ-binding C-terminal domain) form heteromers with other Kir3 subunits (Kir3.1, 3.2, 3.4) but alter G protein activation kinetics and diminish heteromeric channel assembly. Cloning; electrophysiology in Xenopus oocytes; RT-PCR tissue distribution Brain research. Molecular brain research Low 9191093
1996 GIRK1 protein is present in soma, dendrites, dendritic spines, axons, and nerve terminals of specific brain neurons; immunoelectron microscopy localized GIRK1 adjacent to excitatory postsynaptic densities in dendritic spines of CA1 pyramidal cells, consistent with postsynaptic inhibition of excitatory inputs. Electron microscopic immunocytochemistry; antibody against C-terminus of GIRK1 in rat brain The Journal of neuroscience Medium 8604043 9023373
1999 Reactive oxygen species (O2•- generated by hypoxanthine/xanthine oxidase) activate GIRK1 channels expressed in Xenopus oocytes in a G protein-independent manner; this superoxide-induced current is blocked by Ba2+ but not catalase, indicating direct redox activation of GIRK1. Two-electrode voltage clamp in Xenopus oocytes; pharmacological dissection; chemiluminescence measurement of H2O2 Free radical biology & medicine Low 9895214
2001 Long-term desensitization of cardiac IKACh channels involves the channel itself (GIRK1/GIRK4); channel activity was reduced even when the receptor and G protein were bypassed (using GTPγS or trypsin directly), without detectable internalization of the channel, indicating the channel is functionally modified during desensitization. Cell-attached and inside-out patch clamp in cultured neonatal rat atrial cells; long-term carbachol pre-treatment American journal of physiology. Heart and circulatory physiology Medium 11356610
1999 Co-expression of GIRK1 with GIRK2wv (weaver mutant) in an alternating array tetramer produced K+-selective, G protein-dependent currents, demonstrating that GIRK1 rescues the weaver non-selective phenotype and that adjacent positions of mutant subunits determine phenotypic outcome. Linked dimer/tetramer constructs; electrophysiology in Xenopus oocytes The Journal of neuroscience Medium 10493734
2013 Nogo receptor 1 (NgR1) knockdown by siRNA increased GIRK1 protein and GABAB receptor protein levels in the plasma membrane (assessed by surface biotinylation) via a rapamycin-sensitive (mTOR-dependent) translational mechanism, without changing mRNA levels. siRNA knockdown; cell surface biotinylation; Western blotting; rapamycin pharmacology; NgR1 knockout mice Molecular brain Low 23829864
2020 GAT1508, a bromothiophene-substituted small molecule, specifically activates brain GIRK1/2 but not cardiac GIRK1/4 channels; mutagenesis validated a predicted GAT1508-binding site in GIRK1; GAT1508 acts as an allosteric modulator of channel-PIP2 interactions; in brain slices, it directly stimulated GIRK currents in the basolateral amygdala and facilitated fear extinction in rodents. Chemical screening; electrophysiology; mutagenesis; computational modeling; brain slice recordings; behavioral fear conditioning assays The Journal of biological chemistry Medium 31953327
2020 GIRK1 null mice and YFP-GIRK1 knockin mice (which form correctly assembled but functionally impaired channels) both exhibited impaired spatial learning and memory (Morris water maze), blunted depotentiation following LTP in hippocampal slices, and altered nociception, establishing that GIRK1-containing heterotetramers are required for synaptic plasticity and spatial memory. Knockout and knockin mice; behavioral assays; hippocampal LTP/depotentiation recordings; patch-clamp electrophysiology The Journal of physiology Medium 33124684

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution. Cell 300 12507423
1995 Evidence that direct binding of G beta gamma to the GIRK1 G protein-gated inwardly rectifying K+ channel is important for channel activation. Neuron 290 7576656
2007 Crystal structure of a Kir3.1-prokaryotic Kir channel chimera. The EMBO journal 242 17703190
2005 Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification. Nature neuroscience 240 15723059
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
1995 Molecular cloning of a mouse G-protein-activated K+ channel (mGIRK1) and distinct distributions of three GIRK (GIRK1, 2 and 3) mRNAs in mouse brain. Biochemical and biophysical research communications 162 7702616
1996 Cloning of a Xenopus laevis inwardly rectifying K+ channel subunit that permits GIRK1 expression of IKACh currents in oocytes. Neuron 161 8789957
1997 Probing the G-protein regulation of GIRK1 and GIRK4, the two subunits of the KACh channel, using functional homomeric mutants. The Journal of biological chemistry 145 9395492
1995 Activation of inwardly rectifying potassium channels (GIRK1) by co-expressed rat brain cannabinoid receptors in Xenopus oocytes. Neuroscience letters 127 7777206
1996 G-protein-gated inward rectifier K+ channel proteins (GIRK1) are present in the soma and dendrites as well as in nerve terminals of specific neurons in the brain. The Journal of neuroscience : the official journal of the Society for Neuroscience 119 8604043
2006 Heterotrimeric G proteins form stable complexes with adenylyl cyclase and Kir3.1 channels in living cells. Journal of cell science 116 16787947
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
1995 Identification of structural elements involved in G protein gating of the GIRK1 potassium channel. Neuron 115 7576657
1995 Agonist-induced desensitization of the mu opioid receptor-coupled potassium channel (GIRK1). The Journal of biological chemistry 105 7822283
2002 Contribution of the Kir3.1 subunit to the muscarinic-gated atrial potassium channel IKACh. The Journal of biological chemistry 93 12374786
2001 Distribution of the muscarinic K+ channel proteins Kir3.1 and Kir3.4 in the ventricle, atrium, and sinoatrial node of heart. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 87 11561006
1995 G beta gamma directly binds to the carboxyl terminus of the G protein-gated muscarinic K+ channel, GIRK1. Biochemical and biophysical research communications 86 7626088
1997 GIRK1 immunoreactivity is present predominantly in dendrites, dendritic spines, and somata in the CA1 region of the hippocampus. Proceedings of the National Academy of Sciences of the United States of America 82 9023373
2019 Mutant KCNJ3 and KCNJ5 Potassium Channels as Novel Molecular Targets in Bradyarrhythmias and Atrial Fibrillation. Circulation 74 30764634
1997 Coupling of rat somatostatin receptor subtypes to a G-protein gated inwardly rectifying potassium channel (GIRK1). FEBS letters 71 9426226
1997 Opioid receptors from a lower vertebrate (Catostomus commersoni): sequence, pharmacology, coupling to a G-protein-gated inward-rectifying potassium channel (GIRK1), and evolution. Proceedings of the National Academy of Sciences of the United States of America 65 9223341
2003 Mapping the Gbetagamma-binding sites in GIRK1 and GIRK2 subunits of the G protein-activated K+ channel. The Journal of biological chemistry 63 12743112
2001 Overexpression of the G-protein inwardly rectifying potassium channel 1 (GIRK1) in primary breast carcinomas correlates with axillary lymph node metastasis. Cancer research 61 11212253
2003 Molecular basis of ion selectivity, block, and rectification of the inward rectifier Kir3.1/Kir3.4 K(+) channel. The Journal of biological chemistry 57 14504281
2000 Inhibition of a Gi-activated potassium channel (GIRK1/4) by the Gq-coupled m1 muscarinic acetylcholine receptor. The Journal of biological chemistry 52 11060307
2004 Coordination of membrane excitability through a GIRK1 signaling complex in the atria. The Journal of biological chemistry 51 15037627
1996 A novel ubiquitously distributed isoform of GIRK2 (GIRK2B) enhances GIRK1 expression of the G-protein-gated K+ current in Xenopus oocytes. Biochemical and biophysical research communications 51 8573147
1996 Localization and interaction of epitope-tagged GIRK1 and CIR inward rectifier K+ channel subunits. Neuropharmacology 51 8938714
2010 Evidence for oligomerization between GABAB receptors and GIRK channels containing the GIRK1 and GIRK3 subunits. The European journal of neuroscience 48 20846323
2010 NMR analyses of the Gbetagamma binding and conformational rearrangements of the cytoplasmic pore of G protein-activated inwardly rectifying potassium channel 1 (GIRK1). The Journal of biological chemistry 46 21075842
2009 Divergent regulation of GIRK1 and GIRK2 subunits of the neuronal G protein gated K+ channel by GalphaiGDP and Gbetagamma. The Journal of physiology 46 19470775
1998 Human D2 and D4 dopamine receptors couple through betagamma G-protein subunits to inwardly rectifying K+ channels (GIRK1) in a Xenopus oocyte expression system: selective antagonism by L-741,626 and L-745,870 respectively. Neuropharmacology 46 9833627
2003 Contribution of Kir3.1, Kir3.2A and Kir3.2C subunits to native G protein-gated inwardly rectifying potassium currents in cultured hippocampal neurons. The European journal of neuroscience 45 14622172
2012 Conformational dynamics of Kir3.1/Kir3.2 channel activation via δ-opioid receptors. Molecular pharmacology 44 23175530
2011 Association study of the KCNJ3 gene as a susceptibility candidate for schizophrenia in the Chinese population. Human genetics 43 21927946
1995 Colocalization of mu opioid receptors with GIRK1 potassium channels in the rat brain: an immunocytochemical study. Receptors & channels 43 8821795
1995 Inhibition of function in Xenopus oocytes of the inwardly rectifying G-protein-activated atrial K channel (GIRK1) by overexpression of a membrane-attached form of the C-terminal tail. Proceedings of the National Academy of Sciences of the United States of America 36 7542774
2010 Gating of a G protein-sensitive mammalian Kir3.1 prokaryotic Kir channel chimera in planar lipid bilayers. The Journal of biological chemistry 35 20937804
2005 PKC-delta sensitizes Kir3.1/3.2 channels to changes in membrane phospholipid levels after M3 receptor activation in HEK-293 cells. American journal of physiology. Cell physiology 35 15857907
1994 G protein-activated inwardly rectifying potassium channel (GIRK1/KGA) mRNA in adult rat heart and brain by in situ hybridization histochemistry. Molecular and cellular neurosciences 34 7704424
1994 Human G-protein-coupled inwardly rectifying potassium channel (GIRK1) gene (KCNJ3): localization to chromosome 2 and identification of a simple tandem repeat polymorphism. Genomics 34 8088798
2006 Blockade by NIP-142, an antiarrhythmic agent, of carbachol-induced atrial action potential shortening and GIRK1/4 channel. Journal of pharmacological sciences 33 16891768
1997 Genomic organization and promoter analysis of the human G-protein-coupled K+ channel Kir3.1 (KCNJ3/HGIRK1). Genomics 30 9119365
2020 The small molecule GAT1508 activates brain-specific GIRK1/2 channel heteromers and facilitates conditioned fear extinction in rodents. The Journal of biological chemistry 29 31953327
1996 G protein-gated K+ channel (GIRK1) protein is expressed presynaptically in the paraventricular nucleus of the hypothalamus. Biochemical and biophysical research communications 29 8645300
2014 Recruitment of Gβγ controls the basal activity of G-protein coupled inwardly rectifying potassium (GIRK) channels: crucial role of distal C terminus of GIRK1. The Journal of physiology 27 25384780
1999 The dual modulation of GIRK1/GIRK2 channels by opioid receptor ligands. European journal of pharmacology 27 10607882
2013 A computational model predicts that Gβγ acts at a cleft between channel subunits to activate GIRK1 channels. Science signaling 26 23943609
2011 Hesperidin induces antinociceptive effect in mice and its aglycone, hesperetin, binds to μ-opioid receptor and inhibits GIRK1/2 currents. Pharmacology, biochemistry, and behavior 25 21624389
2000 Glycosylation of GIRK1 at Asn119 and ROMK1 at Asn117 has different consequences in potassium channel function. The Journal of biological chemistry 24 10889209
2000 Residues and mechanisms for slow activation and Ba2+ block of the cardiac muscarinic K+ channel, Kir3.1/Kir3.4. The Journal of biological chemistry 24 10956662
2018 GIRK1-mediated inwardly rectifying potassium current suppresses the epileptiform burst activities and the potential antiepileptic effect of ML297. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 23 29499411
2012 Structural elements in the Girk1 subunit that potentiate G protein-gated potassium channel activity. Proceedings of the National Academy of Sciences of the United States of America 22 23236146
2010 Cloning and characterisation of GIRK1 variants resulting from alternative RNA editing of the KCNJ3 gene transcript in a human breast cancer cell line. Journal of cellular biochemistry 22 20512921
1995 Functional expression of an epitope-tagged G protein-coupled K+ channel (GIRK1). The Journal of biological chemistry 22 7540174
2003 Single channel analysis of the regulation of GIRK1/GIRK4 channels by protein phosphorylation. Biophysical journal 21 12547819
1997 Cloning and characterization of Kir3.1 (GIRK1) C-terminal alternative splice variants. Brain research. Molecular brain research 21 9191093
1997 A C-terminal peptide of the GIRK1 subunit directly blocks the G protein-activated K+ channel (GIRK) expressed in Xenopus oocytes. The Journal of physiology 21 9409468
2003 The selectivity filter may act as the agonist-activated gate in the G protein-activated Kir3.1/Kir3.4 K+ channel. The Journal of biological chemistry 20 14525972
2004 K+ activation of kir3.1/kir3.4 and kv1.4 K+ channels is regulated by extracellular charges. Biophysical journal 19 15454439
2000 Changes in GIRK1/GIRK2 deactivation kinetics and basal activity in the presence and absence of RGS4. Life sciences 19 11065178
2016 The GIRK1 subunit potentiates G protein activation of cardiac GIRK1/4 hetero-tetramers. eLife 18 27074664
2015 A Quantitative Model of the GIRK1/2 Channel Reveals That Its Basal and Evoked Activities Are Controlled by Unequal Stoichiometry of Gα and Gβγ. PLoS computational biology 18 26544551
2005 Neuronal Kir3.1/Kir3.2a channels coupled to serotonin 1A and muscarinic m2 receptors are differentially modulated by the "short" RGS3 isoform. Neuropharmacology 18 15935408
1995 Involvement of G-protein alpha il subunits in activation of G-protein gated inward rectifying K+ channels (GIRK1) by human NPY1 receptors. British journal of pharmacology 18 8581266
2017 Discovery and Characterization of 1H-Pyrazol-5-yl-2-phenylacetamides as Novel, Non-Urea-Containing GIRK1/2 Potassium Channel Activators. ACS chemical neuroscience 16 28697302
1999 Alteration in expression of G-protein-activated inward rectifier K+-channel subunits GIRK1 and GIRK2 in the rat brain following electroconvulsive shock. Neuroscience 16 10215164
2016 Overexpression of KCNJ3 gene splice variants affects vital parameters of the malignant breast cancer cell line MCF-7 in an opposing manner. BMC cancer 15 27519272
2000 Mutation analysis of the inwardly rectifying K(+) channels KCNJ6 (GIRK2) and KCNJ3 (GIRK1) in juvenile myoclonic epilepsy. American journal of medical genetics 14 10686544
2020 Codon Harmonization of a Kir3.1-KirBac1.3 Chimera for Structural Study Optimization. Biomolecules 13 32164257
2009 Heteromeric assembly of inward rectifier channel subunit Kir2.1 with Kir3.1 and with Kir3.4. Biochemical and biophysical research communications 13 19338762
2000 Kir3.1/3.2 encodes an I(KACh)-like current in gastrointestinal myocytes. American journal of physiology. Gastrointestinal and liver physiology 13 10666054
2010 A real-time screening assay for GIRK1/4 channel blockers. Journal of biomolecular screening 12 20938046
2000 Expression of GIRK (Kir3.1/Kir3.4) channels in mouse fibroblast cells with and without beta1 integrins. FEBS letters 12 10682853
1997 ATP-dependent regulation of a G protein-coupled K+ channel (GIRK1/GIRK4) expressed in oocytes. The American journal of physiology 12 9038938
2021 Analgesic α-conotoxins modulate native and recombinant GIRK1/2 channels via activation of GABAB receptors and reduce neuroexcitability. British journal of pharmacology 11 34599513
2020 Reduced activity of GIRK1-containing heterotetramers is sufficient to affect neuronal functions, including synaptic plasticity and spatial learning and memory. The Journal of physiology 11 33124684
2012 Chronic effects of corticosterone on GIRK1-3 subunits and 5-HT1A receptor expression in rat brain and their reversal by concurrent fluoxetine treatment. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 11 22591911
2001 Cloning and characterization of G protein-gated inward rectifier K+ channel (GIRK1) isoforms from heart and brain. Journal of molecular neuroscience : MN 11 11345517
2014 Prenatal protein malnutrition decreases KCNJ3 and 2DG activity in rat prefrontal cortex. Neuroscience 10 25446346
2001 Evidence of involvement of GIRK1/GIRK4 in long-term desensitization of cardiac muscarinic K+ channels. American journal of physiology. Heart and circulatory physiology 10 11356610
2020 GIRK1-Mediated Inwardly Rectifying Potassium Current Is a Candidate Mechanism Behind Purkinje Cell Excitability, Plasticity, and Neuromodulation. Cerebellum (London, England) 9 32617840
1999 The inwardly rectifying K(+) channel subunit GIRK1 rescues the GIRK2 weaver phenotype. The Journal of neuroscience : the official journal of the Society for Neuroscience 9 10493734
2014 Differential effects of genetically-encoded Gβγ scavengers on receptor-activated and basal Kir3.1/Kir3.4 channel current in rat atrial myocytes. Cellular signalling 8 24576551
2001 The expression of G-protein-gated inwardly rectifying K+ channels GIRK1 and GIRK2 mRNAs in the supraoptic nucleus of the rat and possible role involved. Neuroreport 8 11303735
2022 Use of a Molecular Switch Probe to Activate or Inhibit GIRK1 Heteromers In Silico Reveals a Novel Gating Mechanism. International journal of molecular sciences 7 36142730
2017 Inhibition of 17-beta-estradiol on neuronal excitability via enhancing GIRK1-mediated inwardly rectifying potassium currents and GIRK1 expression. Journal of the neurological sciences 7 28320163
2013 Molecular basis of the facilitation of the heterooligomeric GIRK1/GIRK4 complex by cAMP dependent protein kinase. Biochimica et biophysica acta 7 23305758
2013 Post-transcriptional regulation of GABAB receptor and GIRK1 channels by Nogo receptor 1. Molecular brain 7 23829864
2006 Base of pore loop is important for rectification, activation, permeation, and block of Kir3.1/Kir3.4. Biophysical journal 7 16513790
2003 Inwardly rectifying Kir3.1 subunit knockdown impairs learning and memory in an olfactory associative task in rat. Brain research. Molecular brain research 7 12750011
2023 Immunoreactivity of Kir3.1, muscarinic receptors 2 and 3 on the brainstem, vagus nerve and heart tissue under experimental demyelination. Brain research bulletin 6 36967090
2020 A Collision Coupling Model Governs the Activation of Neuronal GIRK1/2 Channels by Muscarinic-2 Receptors. Frontiers in pharmacology 6 32903404
2019 Discovery, synthesis and characterization of a series of (1-alkyl-3-methyl-1H-pyrazol-5-yl)-2-(5-aryl-2H-tetrazol-2-yl)acetamides as novel GIRK1/2 potassium channel activators. Bioorganic & medicinal chemistry letters 6 30718161
1999 The cardiac acetylcholine-activated, inwardly rectifying K+-channel subunit GIRK1 gives rise to an inward current induced by free oxygen radicals. Free radical biology & medicine 6 9895214
2017 Knockdown of cardiac Kir3.1 gene with siRNA can improve bradycardia in an experimental sinus bradycardia rat model. Molecular and cellular biochemistry 5 28205094
2016 Critical evaluation of KCNJ3 gene product detection in human breast cancer: mRNA in situ hybridisation is superior to immunohistochemistry. Journal of clinical pathology 5 27698251
2009 Backbone resonance assignments for the cytoplasmic regions of G protein-activated inwardly rectifying potassium channel 1 (GIRK1). Biomolecular NMR assignments 5 19636962
2007 Analysis and mapping of CACNB4, CHRNA1, KCNJ3, SCN2A and SPG4, physiological candidate genes for porcine congenital progressive ataxia and spastic paresis. Journal of animal breeding and genetics = Zeitschrift fur Tierzuchtung und Zuchtungsbiologie 5 17868079
2007 The GIRK1 brain variant GIRK1d and its functional impact on heteromultimeric GIRK channels. Journal of receptor and signal transduction research 5 18097938

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