Affinage

KCNJ5

G protein-activated inward rectifier potassium channel 4 · UniProt P48544

Length
419 aa
Mass
47.7 kDa
Annotated
2026-04-28
100 papers in source corpus 36 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

KCNJ5 encodes the G-protein-gated inwardly rectifying potassium channel subunit Kir3.4 (GIRK4), which is essential for parasympathetic regulation of heart rate, adrenal aldosterone homeostasis, and hypothalamic energy balance. GIRK4 assembles with GIRK1 (Kir3.1) into heterotetrameric IKACh channels—and can also form functional homotetramers—that are gated by direct Gβγ binding to the Kir3.4 C-terminal domain (residues 209–245), with the selectivity filter simultaneously serving as the agonist-activated gate; GIRK4 is additionally required for GIRK1 surface trafficking and mature glycosylation, confers mechanosensitivity to the channel complex, and is regulated by PKA/PP2A phosphorylation cycling (PMID:9642257, PMID:9891030, PMID:9430664, PMID:12547819, PMID:14525972). Somatic or germline mutations near the selectivity filter (e.g., G151R, L168R, T158A) abolish K⁺ selectivity, producing constitutive Na⁺ influx that depolarizes adrenal glomerulosa cells, activates voltage-gated Ca²⁺ channels, and drives CYP11B2-dependent aldosterone overproduction underlying primary aldosteronism, while macrolide antibiotics selectively inhibit these mutant channels (PMID:22308486, PMID:24506072, PMID:28604387). Loss-of-function KCNJ5 variants cause long QT syndrome (LQT13) through reduced Kir3.4 membrane expression or dominant-negative suppression of Kir2.1 currents (PMID:20560207, PMID:24574546).

Mechanistic history

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

    Initial cloning studies resolved a key identity question—whether KCNJ5/CIR encodes a KATP or IKACh subunit—by demonstrating that CIR produces G-protein-gated, not ATP-sensitive, currents and is fully co-immunodepleted with GIRK1 from atrial tissue.

    Evidence Heterologous expression in insect, oocyte, and mammalian cells with patch clamp; immunodepletion from cardiac lysates

    PMID:7499400

    Open questions at the time
    • Stoichiometry of native CIR/GIRK1 complexes not determined
    • No direct binding assay for subunit interaction
  2. 1996 High

    Biochemical and biophysical characterization established that GIRK4 forms obligate heteromultimers with GIRK1 via transmembrane domains and is directly gated by Gβ1γ2 binding to its C-terminal domain with measurable affinity (~800 nM Kd), while cytoplasmic N- and C-terminal domains suffice for G-protein gating.

    Evidence Co-immunoprecipitation, surface plasmon resonance with purified Gβγ, chimera analysis between CIR and IRK1, Xenopus oocyte electrophysiology

    PMID:8858132 PMID:8938714 PMID:8938723

    Open questions at the time
    • Atomic-resolution structure of Gβγ–GIRK4 C-terminus complex not available
    • Relative contributions of N- vs C-terminal Gβγ binding sites not resolved
  3. 1998 High

    Gene knockout and peptide competition studies demonstrated that GIRK4 is physiologically essential—its deletion abolishes half of vagal chronotropic effects and eliminates beat-to-beat heart rate variability—and identified specific C-terminal residues (209–245) as the Gβγ binding/gating interface, with C216 being critical.

    Evidence GIRK4 knockout mice with ECG telemetry; Gβγ competition peptides and point mutations with patch clamp on purified native IKACh

    PMID:9459446 PMID:9642257

    Open questions at the time
    • Contribution of GIRK4 homotetramers vs heteromers to in vivo cardiac phenotype unknown
    • Downstream signaling from GIRK4 to pacemaker gene network not explored
  4. 1998 High

    Two additional functional properties of GIRK4 were established: it forms homotetrameric channels distinct from GIRK1/GIRK4 heteromers in native cardiac tissue, and it confers stretch-inhibition (mechanosensitivity) to the IKACh complex—the first molecularly identified stretch-inactivated K⁺ channel.

    Evidence Immunopurification from bovine atria with single-channel recording; patch clamp on rabbit atrial myocytes and Xenopus oocytes expressing homomeric vs heteromeric channels

    PMID:9430664 PMID:9765280

    Open questions at the time
    • Molecular determinants of mechanosensitivity within GIRK4 not mapped
    • Physiological role of homomeric GIRK4 channels in vivo not defined
  5. 1999 High

    GIRK4 was shown to serve as a chaperone/trafficking factor for GIRK1: GIRK1 cannot reach the plasma membrane or acquire mature glycosylation without GIRK4 co-expression, and GIRK4-KO mouse atrial myocytes lack surface GIRK1, establishing GIRK4 as the obligate trafficking partner.

    Evidence Surface expression assay with Flag-tagged GIRK1, glycosylation analysis, pulse-labeling, C-terminal truncation mapping, GIRK4-KO mouse atrial myocytes

    PMID:9891030

    Open questions at the time
    • ER-export signal within GIRK4 C-terminus not precisely defined
    • Whether GIRK4 trafficking function extends to neuronal GIRK complexes not tested
  6. 2003 High

    Systematic mutagenesis of the selectivity filter revealed that a conserved glutamate-arginine salt bridge behind the filter maintains K⁺ selectivity and that the selectivity filter itself serves as the agonist-activated gate—coupling ion selectivity to G-protein gating in a single structural element.

    Evidence Site-directed mutagenesis of selectivity filter and bundle crossing residues, Xenopus oocyte electrophysiology with muscarinic receptor co-expression, molecular modeling

    PMID:14504281 PMID:14525972

    Open questions at the time
    • No high-resolution structure of open vs closed filter conformations
    • Allosteric pathway from Gβγ binding to filter gating not mapped
  7. 2003 High

    PKA phosphorylation was shown to increase GIRK1/GIRK4 open probability while PP2A dephosphorylation reduces Gβγ sensitivity, establishing a phosphorylation-dependent regulatory axis; the GIRK1 C-terminal 20 residues are required for PP2A-mediated regulation.

    Evidence Single-channel recording on excised inside-out patches with purified PKA and PP2A, C-terminal truncation mutants

    PMID:12547819

    Open questions at the time
    • Specific phosphorylation sites on GIRK4 not identified
    • In vivo relevance of PKA/PP2A regulation to cardiac physiology not demonstrated
  8. 2010 High

    A germline KCNJ5 loss-of-function mutation (G387R) was identified as the cause of congenital long QT syndrome (LQT13), linking GIRK4 channel dysfunction directly to human cardiac arrhythmia through reduced membrane expression.

    Evidence Genome-wide linkage in a 4-generation Chinese family, Sanger sequencing, patch clamp, western blot for surface expression

    PMID:20560207

    Open questions at the time
    • Whether other KCNJ5 loss-of-function variants cause LQT13 not systematically assessed
    • Mechanism by which G387R impairs trafficking not defined
  9. 2012 High

    A convergent series of studies established that somatic and germline KCNJ5 selectivity-filter mutations (G151R, L168R, T158A, I157S) cause primary aldosteronism by abolishing K⁺ selectivity, allowing constitutive Na⁺ influx that depolarizes adrenal glomerulosa cells and activates voltage-gated Ca²⁺ channels to drive CYP11B2-dependent aldosterone overproduction—with genotype-specific lethality explaining clinical heterogeneity.

    Evidence Electrophysiology in HEK293T cells, lentiviral expression in HAC15 adrenal cells, reversal potential measurements, aldosterone secretion assays, nifedipine/W-7 pharmacological blockade, genetic-clinical correlation across multiple kindreds

    PMID:22308486 PMID:22315453 PMID:22628607 PMID:22798349

    Open questions at the time
    • How mutant KCNJ5 drives cell proliferation (adenoma formation) vs just aldosterone secretion not resolved
    • Whether wild-type GIRK4 signals through GPCR in glomerulosa cells not established
  10. 2014 High

    The mechanistic model of mutant KCNJ5-driven aldosteronism was refined: Na⁺ overload not only activates voltage-gated Ca²⁺ channels but also impairs Na⁺/Ca²⁺ exchanger-mediated Ca²⁺ extrusion, compounding the Ca²⁺ signal; separately, a KCNJ5 mutation was shown to cause Andersen-Tawil syndrome via dominant-negative inhibition of Kir2.1, expanding the disease spectrum.

    Evidence Intracellular Na⁺ and Ca²⁺ fluorescent imaging in NCI-H295R cells with pharmacological profiling; Xenopus oocyte co-expression of mutant Kir3.4 with Kir2.1

    PMID:24506072 PMID:24574546

    Open questions at the time
    • Structural basis of mutant Kir3.4–Kir2.1 interaction not defined
    • Whether NCX impairment contributes in vivo to aldosteronism not tested
  11. 2017 High

    A therapeutic strategy emerged when macrolide antibiotics were discovered to selectively inhibit mutant (G151R, L168R) but not wild-type KCNJ5 channels, suppressing CYP11B2 expression and aldosterone production—selectivity arising from the altered conformation of the mutant selectivity filter.

    Evidence High-throughput cell viability screen, patch clamp electrophysiology demonstrating direct channel block, CYP11B2 and aldosterone assays in HAC15 cells

    PMID:28604387

    Open questions at the time
    • No in vivo efficacy data for macrolide treatment of aldosterone-producing adenomas
    • Binding site of macrolides on mutant channel not resolved at atomic level
  12. 2019 Medium

    Post-transcriptional regulation of KCNJ5 was established: miR-221 and miR-222 directly target the KCNJ5 3′-UTR to reduce channel protein and current density, providing a mechanism for cardiac electrical remodeling under pathological conditions.

    Evidence 3′-UTR luciferase reporter assay, RNA-seq, western blot, whole-cell patch clamp in cardiomyocytes

    PMID:31312877

    Open questions at the time
    • In vivo relevance of miR-221/222 to KCNJ5 regulation in arrhythmia models not demonstrated
    • Other miRNAs targeting KCNJ5 not systematically surveyed
  13. 2022 High

    A GIRK4-selective small-molecule activator (3hi2one-G4) was developed, defining its binding site at the TM1/TM2/slide helix interface near the PIP2 site, with L77 as the isoform-selectivity determinant—providing the first subunit-selective pharmacological tool for GIRK4.

    Evidence Molecular modeling, site-directed mutagenesis of slide helix and TM residues, electrophysiology in heterologous system

    PMID:35525275

    Open questions at the time
    • No in vivo testing of 3hi2one-G4
    • Whether GIRK4-selective activation has therapeutic utility in cardiac or adrenal disease not explored

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of Gβγ-to-selectivity-filter gating transmission, the mechanism by which mutant KCNJ5 drives adrenal cell proliferation beyond aldosterone excess, and whether GIRK4 homotetramers have distinct physiological roles in vivo.
  • No cryo-EM or crystal structure of full-length GIRK4 in open/closed states
  • Proliferative signaling downstream of mutant KCNJ5 Na⁺/Ca²⁺ influx not characterized
  • Physiological function of homomeric GIRK4 channels in heart or brain not established in vivo

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 5 GO:0140299 molecular sensor activity 1
Localization
GO:0005886 plasma membrane 4
Pathway
R-HSA-1643685 Disease 4 R-HSA-382551 Transport of small molecules 4 GO:0060089 molecular transducer activity 3 R-HSA-112316 Neuronal System 3 R-HSA-162582 Signal Transduction 3
Partners
GNB1GNG2KCNJ2KCNJ3
Complex memberships
IKACh (Kir3.1/Kir3.4 heterotetramer)Kir3.4 homotetramer

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 GIRK4 (KCNJ5) is an essential subunit of the cardiac IKACh channel; genetic knockout of GIRK4 in mice abolishes approximately half of the negative chronotropic effects of vagal stimulation and adenosine on heart rate, and eliminates beat-to-beat heart rate variability, establishing GIRK4's required role in cardiac pacemaker regulation. Targeted gene disruption (GIRK4 knockout mice), ECG telemetry, pharmacological manipulation in vivo Neuron High 9459446
1996 GIRK4 (KCNJ5/CIR) forms functional heteromultimeric G-protein-gated inwardly rectifying K+ channels with GIRK1, demonstrated by co-immunoprecipitation of epitope-tagged subunits from metabolically labeled cells, and by immunofluorescence showing GIRK1 plasma membrane localization only when co-expressed with CIR. Co-immunoprecipitation, immunofluorescence, Xenopus oocyte expression with G-protein-gated current recordings Neuropharmacology High 8938714
1998 Gβγ binding to the GIRK4 subunit is critical for IKACh activation: peptides from GIRK4 amino acids 209–225 and 226–245 compete for Gβγ binding to native IKACh; a single point mutation C216T in GIRK4 dramatically reduces Gβγ binding and channel activation; converting 5 residues in GIRK4 (226–245) to those of G-protein-insensitive IRK1 abolishes Gβγ binding and activation. Gβγ binding competition with synthetic peptides, mutational analysis, purified native IKACh, functional expression in mammalian cells with patch clamp The Journal of biological chemistry High 9642257
1997 GIRK1 and GIRK4 interact in a qualitatively similar way with G-protein subunits; the functionally important Gβγ interaction sites reside within homologous (H5/pore) regions of both subunits rather than divergent terminal regions, as demonstrated using gain-of-function homomeric mutants GIRK1(F137S) and GIRK4(S143T) expressed in Xenopus oocytes. Site-directed mutagenesis, Xenopus oocyte expression, two-electrode voltage clamp, co-expression with muscarinic receptors and G-protein subunits The Journal of biological chemistry High 9395492
1999 GIRK4 is required for cell-surface localization and mature glycosylation of GIRK1: GIRK1 expressed alone is retained intracellularly as core-glycosylated/non-glycosylated forms; co-expression of GIRK4 causes appearance of mature glycosylated GIRK1 at the plasma membrane. A 25-amino-acid region in the GIRK4 C-terminus is required for surface targeting of GIRK1/GIRK4 heteromers, and another 25-aa region for GIRK4 homomers. In atrial myocytes from GIRK4-KO mice, GIRK1 is absent from the surface and immature. Flag-tagged GIRK1 surface expression assay, glycosylation analysis, [35S]methionine pulse-labeling, truncation/chimera analysis, GIRK4-KO mouse atrial myocytes The Journal of biological chemistry High 9891030
1998 GIRK4 (KCNJ5) forms homotetrameric complexes in bovine heart atria that are distinct from GIRK1/GIRK4 heterotetramers; approximately half of cardiac GIRK4 exists as GIRK1-free high-molecular-weight SDS-resistant complexes (GIRK4 homotetramers), which form channels with unusual single-channel behavior. Immunopurification from bovine heart atria, SDS-PAGE, single-channel electrophysiology The Journal of biological chemistry High 9765280
1995 GIRK4 (CIR) does not form the cardiac ATP-sensitive K+ channel (IKATP): CIR expression in insect, oocyte, and mammalian cells produces strongly inwardly rectifying, G-protein-regulated K+ currents—not ATP-sensitive currents. CIR protein is restricted to atria (not ventricle) and is completely co-immunodepleted with GIRK1, establishing CIR as exclusively a subunit of IKACh. Heterologous expression in multiple cell systems, patch clamp, immunodepletion with anti-GIRK1 antibody, tissue distribution analysis The Journal of biological chemistry High 7499400
1996 GIRK4 (KCNJ5) expressed in Xenopus oocytes yields functional G-protein-gated inwardly rectifying K+ channels whose activity is enhanced by serotonin 1A receptor stimulation; GIRK4 potentiates currents of other GIRK channels, consistent with channel heteromerization. No ATP sensitivity or KATP pharmacology is observed. Xenopus oocyte expression, two-electrode voltage clamp, receptor co-expression, COS-7 cell expression The Journal of neuroscience Medium 8558261
1996 The N- and C-terminal cytoplasmic domains of GIRK4 (CIR) are sufficient for Gβ1γ2 gating, while the core transmembrane region is critical for heteromultimer formation with GIRK1 (not the cytoplasmic termini), as determined by chimera analysis between CIR and IRK1. CIR/IRK1 chimera construction, Xenopus oocyte expression, electrophysiology Biochemical and biophysical research communications Medium 8858132
1996 Gβ1γ2 binds directly to the C-terminal domain of Kir3.4 (GIRK4, residues 186–419) with a dissociation rate of ~0.003 s⁻¹ and estimated Kd ~800 nM, as measured in real time by surface plasmon resonance biosensor; association kinetics show a concentration-independent slow component (~50 s) suggesting conformational changes during binding. Surface plasmon resonance (biosensor chip), GST-fusion of Kir3.4 C-terminus, purified recombinant Gβ1γ2 Neuropharmacology High 8938723
1998 Kir3.4 (GIRK4) confers mechanosensitivity (stretch-inhibition) to the cardiac muscarinic K+ channel: rabbit atrial IKACh is rapidly and reversibly inhibited by membrane stretch; heteromeric Kir3.1/Kir3.4 channels expressed in Xenopus oocytes recapitulate this mechanosensitivity, and homomeric Kir3.4 channels alone reproduce it—identifying Kir3.4 as the mechanosensitive subunit and making it the first stretch-inactivated K+ channel identified molecularly. Patch clamp on rabbit atrial myocytes, Xenopus oocyte expression of heteromeric and homomeric channels, hypo-osmolar stress protocol The Journal of biological chemistry High 9430664
2001 Overexpression of GIRK4 monomers or multimers in adult rat atrial myocytes produces functional homomeric Kir3.4 channels that interact with Gβγ subunits, demonstrating that GIRK4 homotetramers form functional G-protein-gated channels; these homomeric channels lack fast desensitization and show reduced inward rectification compared to native GIRK1/GIRK4 heteromeric channels. Adenoviral transfection of adult rat atrial myocytes, concatemeric GIRK4 constructs, patch clamp electrophysiology, heterologous expression in CHO and HEK293 cells The Journal of biological chemistry High 11384974
2003 Mutation of charged glutamate-arginine residues behind the selectivity filter of Kir3.1/Kir3.4 reduces or abolishes K+ selectivity; molecular modeling shows these residues form a salt bridge ('bowstring') that maintains the rigid bow-like structure of the selectivity filter restricting permeation to K+; disruption of the salt bridge enhances p-loop flexibility, allowing permeation of other cations and abolishing polyamine-induced inward rectification. Site-directed mutagenesis, electrophysiology in Xenopus oocytes, molecular modeling The Journal of biological chemistry High 14504281
2003 The selectivity filter of the Kir3.1/Kir3.4 channel acts as the agonist-activated gate: mutations that increase selectivity filter flexibility (disrupting the glutamate-arginine salt bridge) abolish both K+ selectivity and agonist activation; mutations within the filter altering selectivity also alter agonist activation; bundle crossing phenylalanine mutations also alter both, indicating coupling between gate and selectivity filter. Site-directed mutagenesis of selectivity filter and bundle crossing residues, electrophysiology in Xenopus oocytes, muscarinic receptor co-expression The Journal of biological chemistry High 14525972
2003 GIRK1/GIRK4 channel activity is regulated by phosphorylation/dephosphorylation: PKA phosphorylation increases open probability and frequency of openings while reducing dwell time in long-closed state; PP2A dephosphorylation reduces apparent G-protein affinity (reduces Gβγ sensitivity); the last 20 C-terminal amino acids of GIRK1 are required for the PP2A-mediated reduction in Gβγ affinity. Single-channel recordings on inside-out patches from Xenopus oocytes, application of purified PKA catalytic subunit and PP2A, C-terminal truncation mutants Biophysical journal High 12547819
2010 A loss-of-function mutation in KCNJ5 (Kir3.4-Gly387Arg) causes congenital long QT syndrome (LQT13): the mutation is present in all affected family members of a 4-generation Chinese family, produces a loss-of-function electrophysiological phenotype, and results in reduced plasma membrane expression of Kir3.4. Genome-wide linkage analysis, Sanger sequencing, western blotting, patch-clamp electrophysiology in heterologous expression system American journal of human genetics High 20560207
2012 Somatic KCNJ5 mutations (G151R, L168R) alter the channel selectivity filter, producing increased Na+ conductance and membrane depolarization in adrenal glomerulosa cells; different mutations at the same residue (G151R vs G151E) produce different degrees of Na+ conductance—G151E causes more extreme Na+-dependent cell lethality limiting adrenocortical cell mass, explaining milder clinical phenotype despite more severe biophysical defect. Electrophysiology of channels expressed in HEK293T cells, Sanger sequencing of familial and adenoma DNA, clinical phenotyping of four kindreds Proceedings of the National Academy of Sciences of the United States of America High 22308486
2012 The KCNJ5 T158A mutation in the selectivity filter region expressed via lentiviral transduction in HAC15 adrenal cortical carcinoma cells causes 5.3-fold increase in aldosterone secretion; the mutated channel decreases plasma membrane polarization allowing Na+ and Ca2+ influx; the effects are blocked by calcium channel antagonist nifedipine and calmodulin inhibitor W-7. Lentiviral expression, aldosterone secretion assay, membrane potential measurement, pharmacological inhibition in HAC15 cells Endocrinology High 22315453
2012 The I157S KCNJ5 germline mutation results in loss of ion selectivity (Na+ permeability), cell membrane depolarization, increased Ca2+ entry in adrenal glomerulosa cells, and increased aldosterone synthesis, as demonstrated by electrophysiological studies of reversal potentials in transfected cells. Sanger sequencing, electrophysiological measurement of reversal potentials in transfected cells The Journal of clinical endocrinology and metabolism Medium 22628607
2012 Wild-type KCNJ5/Kir3.4 maintains resting membrane potential in adrenal glomerulosa cells; angiotensin II down-regulates KCNJ5 mRNA and protein expression, and pharmacological activation of Kir3.4 by naringin inhibits angiotensin II-stimulated membrane depolarization and aldosterone secretion; overexpression of wild-type KCNJ5 decreases membrane voltage, intracellular calcium, steroidogenic enzyme expression, and aldosterone synthesis. siRNA knockdown, lentiviral overexpression, membrane voltage measurements, aldosterone assay, mRNA quantification in HAC15 cells Endocrinology Medium 22798349
2013 The Y152C germline KCNJ5 mutation causes pathological Na+ permeability, cell membrane depolarization, disturbed intracellular Ca2+ homeostasis, and increased CYP11B2 and NR4A2 expression in HAC15 adrenal cells; the CYP11B2 induction is Ca2+-dependent as it is abolished by nifedipine. Electrophysiology, intracellular Ca2+ measurement, gene expression analysis, nifedipine pharmacological inhibition in HAC15 cells The Journal of clinical endocrinology and metabolism Medium 24037882
2014 Mutant KCNJ5 (G151R/L168R) channels cause increased intracellular Na+ (2-fold) and substantial rise in intracellular Ca2+ in NCI-H295R adrenocortical cells; Ca2+ increase results both from activation of voltage-gated Ca2+ channels and from impairment of Ca2+ extrusion by Na+/Ca2+ exchangers; mutated KCNJ5 exhibits altered pharmacology—less sensitive to Ba2+ and tertiapin-Q but inhibited by verapamil and amiloride. Intracellular Na+ and Ca2+ fluorescent dye measurements, pharmacological profiling, patch clamp in NCI-H295R cells Endocrinology High 24506072
2014 A KCNJ5 mutation in Kir3.4 (unnamed in Andersen-Tawil syndrome patient) causes Andersen-Tawil syndrome by inhibiting Kir2.1 channel function; co-expression of mutant Kir3.4 with Kir2.1 in Xenopus oocytes significantly reduces Kir2.1 inwardly rectifying current compared to wild-type Kir3.4, suggesting a dominant-negative interaction between mutant KCNJ5 and KCNJ2. Exome sequencing, Xenopus oocyte expression, two-electrode voltage clamp, immunoblotting in human heart and skeletal muscle Neurology Medium 24574546
2014 Genetic deletion of GIRK4 (KCNJ5) rescues cardiac arrhythmia caused by conditional silencing of HCN4 (funny current) in mice, restoring impulse generation and conduction without impairing heartbeat regulation, demonstrating that GIRK4-containing channels are the critical downstream effectors of the autonomic nervous system whose activity must be balanced against If in sinoatrial pacemaking. Double genetic mouse model (dominant-negative HCN4 plus GIRK4 knockout), ECG, sinoatrial node Ca2+ imaging Nature communications High 25144323
2015 Novel KCNJ5 mutations R115W and E246G reduce Kir3.4 membrane abundance without abolishing K+ selectivity or G-protein activation, and exert dominant-negative effects on wild-type channels; E145Q conducts a Ba2+-insensitive Na+-leak current; inhibition of endogenous Kir3.4 by tertiapin-Q depolarizes membrane potential and increases CYP11B2 expression in human adrenocortical cells, demonstrating that basal Kir3.4 current suppresses aldosterone synthesis. KCNJ5 sequencing, Xenopus oocyte electrophysiology, surface biotinylation assay, tertiapin-Q pharmacology in human adrenocortical cells The Journal of clinical endocrinology and metabolism High 25347571
2015 The E145Q KCNJ5 germline de novo mutation causes Na+-dependent depolarization of adrenal cells and increased intracellular Ca2+, activating NR4A2 transcription factor and CYP11B2 expression; the mutant channel is insensitive to tertiapin-Q and verapamil. Patch clamp, intracellular Ca2+ measurement, gene expression, pharmacological profiling in human adrenocortical cells The Journal of clinical endocrinology and metabolism Medium 25322277
2016 Mutant KCNJ5 (T158A) activates both acute and chronic aldosterone biosynthetic pathways: it increases StAR (acute regulator) expression and phosphorylation, upregulates CYP11B2 transcriptional regulators NURR1 and ATF2, and increases aldosterone, 18-hydroxycortisol, and 18-oxocortisol synthesis; all effects are blocked by the L-type Ca2+ channel blocker verapamil. Doxycycline-inducible expression in HAC15 cells, electrophysiology, steroid LC-MS/MS, gene expression, pharmacological inhibition Journal of molecular endocrinology High 27099398
2017 Macrolide antibiotics (including roxithromycin and idremcinal) selectively inhibit mutant KCNJ5 (G151R and L168R) channels but not wild-type KCNJ5: electrophysiology demonstrates direct channel inhibition; in aldosterone-producing adrenocortical cancer cells, macrolides inhibit KCNJ5-mutant-induced CYP11B2 expression and aldosterone production. Selectivity arises from the altered conformation of the mutant selectivity filter. High-throughput screen for rescue of KCNJ5-MUT-induced lethality, patch clamp electrophysiology, CYP11B2 expression and aldosterone assays in HAC15 cells The Journal of clinical investigation High 28604387
2007 The Kir3.4-G247R loss-of-function mutation reduces basal and acetylcholine-induced IKACh current in Xenopus oocytes; the mutation interferes with activation by stimulatory Gβγ subunits; co-expression with wild-type Kir3.4 or Kir3.1 partially compensates the functional deficit. Xenopus oocyte expression, two-electrode voltage clamp, muscarinic receptor co-expression Biochemical and biophysical research communications Medium 17967416
2004 Extracellular arginine residue R155 in the Kir3.4 subunit of Kir3.1/Kir3.4 is required for K+-activation of the channel; mutation of R155 markedly reduces K+ activation and also abolishes Mg2+ block, suggesting this residue acts as a 'guard' regulating K+ access to the selectivity filter. Site-directed mutagenesis, electrophysiology in Xenopus oocytes Biophysical journal Medium 15454439
2007 Overexpression of Kir3.4 in adult rat atrial myocytes via adenoviral gene transfer produces homomeric Kir3.4 channel currents that are activated by intracellular Na+ (≥15 mM) in a G-protein-independent manner; these homomeric channels differ from native heteromeric IKACh in their regulation by PIP2 depletion (resistant) and their tertiapin-Q sensitivity (IC50 0.61 nM vs 12 nM for IKACh). Adenoviral overexpression in adult rat atrial myocytes, patch clamp, receptor-mediated PLC activation, tertiapin-Q pharmacology The Journal of physiology High 17884923
2008 GIRK4 (KCNJ5) in hypothalamic neurons (ventromedial, paraventricular, and arcuate nuclei) contributes to energy homeostasis: GIRK4 knockout mice develop late-onset obesity (~25% heavier by 9 months) attributable to greater body fat, increased food intake tendency, and reduced net energy expenditure. EGFP reporter transgenic mouse to map Girk4 expression, GIRK4 knockout mouse phenotyping, body composition analysis, behavioral feeding assays Proceedings of the National Academy of Sciences of the United States of America High 18523006
2016 Adenosine-induced atrial fibrillation in human hearts is maintained by localized reentrant drivers in lateral right atria with the highest GIRK4 (KCNJ5) protein expression; the superior/middle lateral right atrium has 1.7-fold higher GIRK4 protein than left atrium; tertiapin (selective GIRK blocker) prevents adenosine-induced action potential duration shortening and AF induction. Biatrial optical mapping of coronary-perfused human hearts, immunoblot mapping of atrial regions, tertiapin pharmacology, n=37 hearts Circulation High 27462069
2019 miR-221 and miR-222 directly target the 3'-UTR of KCNJ5, reducing KCNJ5 channel mRNA and protein abundance in cardiomyocytes; enhanced expression of these miRs reduces GIRK4 channel current density, contributing to cardiac electrical remodeling. 3'-UTR luciferase reporter assay, RNA-seq, western blot, whole-cell patch clamp Cellular and molecular life sciences Medium 31312877
2022 A novel small molecule 3hi2one-G4 selectively activates homomeric GIRK4 channels but not GIRK2, GIRK1/2, or GIRK1/4: molecular modeling, mutagenesis, and electrophysiology define its binding site at the transmembrane 1/transmembrane 2/slide helix interface near the PIP2 binding site; the compound activates GIRK4 by strengthening channel-PIP2 interactions; slide helix residue L77 in GIRK4 (vs I82 in GIRK2) is a major determinant of isoform selectivity. Molecular modeling, site-directed mutagenesis, electrophysiology in heterologous expression system The Journal of biological chemistry High 35525275
2019 KCNJ5 encodes the Kir3.4 subunit that combines with Kir3.1 (KCNJ3) to form the cardiac IKACh channel specifically expressed in atria; a gain-of-function KCNJ3 p.N83H mutation increases basal IKACh current even without muscarinic stimulation, and the selective IKACh blocker NIP-151 suppresses this increased current and rescues bradyarrhythmia in transgenic mutant zebrafish, establishing IKACh (Kir3.1/Kir3.4) as pharmacologically tractable for bradyarrhythmia. Whole-exome sequencing, cellular electrophysiology in heterologous system, transgenic zebrafish model, NIP-151 pharmacology Circulation High 30764634

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Abnormal heart rate regulation in GIRK4 knockout mice. Neuron 307 9459446
2015 cir-ITCH plays an inhibitory role in colorectal cancer by regulating the Wnt/β-catenin pathway. PloS one 262 26110611
1999 CIR, a corepressor linking the DNA binding factor CBF1 to the histone deacetylase complex. Proceedings of the National Academy of Sciences of the United States of America 246 9874765
2012 Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism. Hypertension (Dallas, Tex. : 1979) 225 22275527
2012 Hypertension with or without adrenal hyperplasia due to different inherited mutations in the potassium channel KCNJ5. Proceedings of the National Academy of Sciences of the United States of America 191 22308486
2012 Comprehensive re-sequencing of adrenal aldosterone producing lesions reveal three somatic mutations near the KCNJ5 potassium channel selectivity filter. PloS one 150 22848660
2012 Expression and mutations of KCNJ5 mRNA in Japanese patients with aldosterone-producing adenomas. The Journal of clinical endocrinology and metabolism 146 22278422
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 144 9395492
2010 Identification of a Kir3.4 mutation in congenital long QT syndrome. American journal of human genetics 142 20560207
2012 Potassium channel mutant KCNJ5 T158A expression in HAC-15 cells increases aldosterone synthesis. Endocrinology 140 22315453
2013 Somatic ATP1A1, ATP2B3, and KCNJ5 mutations in aldosterone-producing adenomas. Hypertension (Dallas, Tex. : 1979) 135 24082052
2012 Somatic mutations affecting the selectivity filter of KCNJ5 are frequent in 2 large unselected collections of adrenal aldosteronomas. Hypertension (Dallas, Tex. : 1979) 127 22252394
2000 Brain localization and behavioral impact of the G-protein-gated K+ channel subunit GIRK4. The Journal of neuroscience : the official journal of the Society for Neuroscience 99 10908597
2012 A novel point mutation in the KCNJ5 gene causing primary hyperaldosteronism and early-onset autosomal dominant hypertension. The Journal of clinical endocrinology and metabolism 94 22628607
2012 Role of KCNJ5 in familial and sporadic primary aldosteronism. Nature reviews. Endocrinology 90 23229280
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