Affinage

KCNJ16

Inward rectifier potassium channel 16 · UniProt Q9NPI9

Length
418 aa
Mass
47.9 kDa
Annotated
2026-06-10
72 papers in source corpus 35 papers cited in narrative 35 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

KCNJ16 encodes Kir5.1, an inwardly rectifying K+ channel subunit that does not form functional homomeric channels but obligately heteromerizes with members of the Kir4.0 subfamily (Kir4.1/KCNJ10 or Kir4.2/KCNJ15) to generate pH-sensitive basolateral K+ channels (PMID:10764726, PMID:12456399). The defining functional contribution of Kir5.1 is to shift the intracellular pH sensitivity of these heteromers into the physiological range (pKa ~7.45 versus ~6 for homomeric Kir4.1), converting the channel into a K+/pH sensor, with the novel rectification and gating arising from an intersubunit interface between the cytoplasmic domains (PMID:10790154, PMID:10871638, PMID:11306656, PMID:12923169). In the distal convoluted tubule, Kir4.1/Kir5.1 sets the basolateral membrane potential and acts as the upstream sensor that couples dietary Na+, K+, and acid-base status to NCC activity; loss of Kir5.1 abolishes the responsiveness of the DCT to dietary Na+ and K+ and disrupts NCC regulation (PMID:21633011, PMID:30559144, PMID:31239388, PMID:33900854). In the proximal tubule Kir5.1 is required for assembly of the Kir4.2/Kir5.1 50-pS channel that maintains membrane polarization (PMID:39745541). Channel activity is tuned by Nedd4-2-mediated ubiquitination acting through a C-terminal TPVT motif on Kir5.1, by PKC downstream of Gαq-coupled receptors and the calcium-sensing receptor, by β-adrenergic/PKA signaling, by calcineurin/PP2B, by PIP2, and by S-glutathionylation of Cys158 in TM2 during oxidative stress (PMID:29897283, PMID:41886268, PMID:30571558, PMID:36821372, PMID:10871638, PMID:22907060). In the brain, Kir5.1 assembles with Kir4.1 in astrocytes in a region-specific manner and, via PSD-95, can reach the plasma membrane as a homomer (PMID:15310750, PMID:11988170). Loss-of-function mutations in KCNJ16 cause a human tubulopathy comprising hypokalemia, salt wasting, disturbed acid-base homeostasis, and sensorineural deafness (PMID:33811157); in rodents Kcnj16 deletion additionally impairs CO2/O2 chemoreflexes, causes audiogenic seizures, and reduces male fertility (PMID:30605394, PMID:33232300, PMID:34205849).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2000 High

    Established that Kir5.1 is not an autonomous channel but a modulatory subunit that, by heteromerizing with Kir4.1, imposes physiological-range intracellular pH sensitivity on the resulting channel.

    Evidence Heterologous co-expression and voltage clamp in Xenopus oocytes with pH titration and K67M mutagenesis

    PMID:10764726 PMID:10790154 PMID:10871638

    Open questions at the time
    • Did not establish the structural basis of how Kir5.1 raises the pKa
    • Endogenous heteromer composition in native tissue not yet defined
  2. 2000 High

    Resolved how Kir5.1 changes channel biophysics at the single-channel level and how PIP2 modulates pH gating, showing pH acts on open-state probability rather than conductance.

    Evidence Inside-out single-channel patch-clamp in oocytes with exogenous PIP2 and R178/K67 mutagenesis

    PMID:10871638

    Open questions at the time
    • Structural location of the pH-sensing residues not defined
    • PIP2 binding site only mapped to a single residue
  3. 2001 High

    Showed that Kir5.1's partner specificity extends to Kir4.2 and that its assembly differentially reshapes gating depending on partner, distinguishing functional heteromerization from inhibitory silencing of non-partners.

    Evidence Single-channel recording of Kir4.2/Kir5.1 and Kir2.1/Kir5.1 co-expression in oocytes

    PMID:11240146 PMID:11306656

    Open questions at the time
    • Physiological relevance of Kir2.1 silencing in native cells untested
    • Stoichiometry of heteromers not determined
  4. 2002 High

    Defined the selectivity rules for Kir5.1 assembly (Kir4.0 subfamily only) and identified PSD-95 as a scaffold that overcomes Kir5.1's rapid internalization to permit homomeric surface expression in neurons.

    Evidence Co-IP from brain tissue, chimera mutagenesis, and electrophysiology in HEK293T cells with PKA manipulation

    PMID:11988170 PMID:12456399

    Open questions at the time
    • Whether homomeric Kir5.1/PSD-95 channels exist physiologically in vivo unclear
    • PKA phosphorylation site on Kir5.1 not precisely mapped
  5. 2003 High

    Localized the determinants of rectification, gating, and pH sensitivity to an intersubunit interface between the cytoplasmic domains, providing a structural rationale for functional coupling in the heteromer.

    Evidence Site-directed mutagenesis of interface residues with whole-cell and excised-patch electrophysiology in oocytes

    PMID:12923169

    Open questions at the time
    • No high-resolution structure of the heteromeric interface
    • Single lab
  6. 2004 High

    Mapped the in vivo expression of Kir5.1 in astrocytes and cochlear fibrocytes, revealing region-specific co-assembly with Kir4.1 versus spatial segregation, indicating context-dependent channel composition.

    Evidence Immunoprecipitation and subunit-specific immunolabeling in mouse brain and cochlear lateral wall

    PMID:14750965 PMID:15310750

    Open questions at the time
    • Functional consequence of regional heteromer/homomer balance untested
    • Syntrophin role in targeting only correlative
  7. 2008 Medium

    Identified post-translational regulatory inputs (PKC and Gαq-coupled neurotransmitter receptors) that selectively inhibit the heteromer, showing Kir5.1 confers signaling responsiveness absent from homomeric Kir4.1.

    Evidence Tandem-dimer oocyte expression with PMA, GPCR agonists, PKC inhibitors, and in vitro phosphorylation

    PMID:17559083 PMID:17585871

    Open questions at the time
    • PKC phosphorylation sites not definitively mapped due to redundancy
    • Heterologous system; native DCT/neuron validation limited
  8. 2008 High

    Confirmed that Kir4.1/Kir5.1 is the predominant native basolateral K+ channel in collecting duct principal cells and is responsive to dietary salt, linking the channel to renal salt handling.

    Evidence Patch-clamp in native mouse cortical collecting duct with immunohistochemistry, qPCR, and dietary manipulation

    PMID:18367659

    Open questions at the time
    • Causal upstream/downstream relationship to transporters not yet established
    • Cell-type restriction within nephron incomplete
  9. 2010 High

    Demonstrated genetically that Kir5.1 is a required determinant of neuronal pH/PCO2 chemosensitivity, moving the in vitro pH-sensor model into native neurons.

    Evidence Kcnj16 knockout mice with patch-clamp of locus coeruleus neurons under pH manipulation

    PMID:21047793

    Open questions at the time
    • Whether residual Kir4.1 compensates incompletely characterized
    • Link to whole-animal respiratory behavior not yet made
  10. 2011 High

    Established the in vivo renal phenotype of Kir5.1 loss—hypokalemic hyperchloremic metabolic acidosis with enhanced DCT Na+ absorption—defining Kir5.1 as a pH-sensitive regulator of distal salt transport.

    Evidence Kcnj16 knockout mouse metabolic studies, DCT basolateral patch-clamp, and hydrochlorothiazide challenge

    PMID:21633011

    Open questions at the time
    • Mechanism linking basolateral channel to apical NCC not yet defined
    • Acid-base versus salt contributions not fully separated
  11. 2012 High

    Identified S-glutathionylation of Cys158 in TM2 as the molecular mechanism coupling oxidative stress to selective inhibition of the heteromer.

    Evidence Whole-cell/inside-out patch-clamp in HEK cells with C158 mutagenesis, tandem dimers, and biochemical GSH assays

    PMID:22907060

    Open questions at the time
    • In vivo relevance of Cys158 modification untested
    • Physiological oxidant sources not identified
  12. 2013 Medium

    Showed that Kir5.1 modulates the functional output of disease-relevant Kir4.1 mutations, with implications for how KCNJ10 variants are assessed.

    Evidence Co-expression of KCNJ16 with KCNJ10 p.A167V in oocytes with voltage clamp and Western blot

    PMID:24193250

    Open questions at the time
    • Single lab heterologous assay
    • In vivo consequence of suppression untested
  13. 2017 High

    Identified upstream transcriptional control of Kcnj16 by HNF1β, connecting the channel to a developmental/renal transcription factor whose mutations cause kidney disease.

    Evidence ChIP-seq, luciferase promoter assay, siRNA knockdown, and renal HNF1β knockout mouse with qPCR

    PMID:28577853

    Open questions at the time
    • Other transcriptional regulators not surveyed
    • Quantitative link from transcript reduction to channel function not measured
  14. 2017 High

    Demonstrated in a rat model that Kir5.1 loss causes life-threatening salt wasting and placed the channel upstream of ENaC-dependent Na+ transport via pharmacological epistasis.

    Evidence Kcnj16 knockout Dahl SS rat with collecting duct electrophysiology, IHC, dietary challenge, and benzamil/diuretic rescue

    PMID:28931751

    Open questions at the time
    • Mechanism of Kir4.1 cytosolic mislocalization without Kir5.1 unclear
    • Species-specific differences from mouse not reconciled
  15. 2018 High

    Defined Nedd4-2 regulation of the channel, showing it binds the Kir5.1 C-terminal TPVT motif to ubiquitinate Kir4.1 and reduce surface expression—a Kir5.1-dependent degradative control point.

    Evidence Co-IP, GST pulldown, ubiquitination assay, T249A mutagenesis, patch-clamp, and kidney-specific Nedd4-2 KO mice

    PMID:29897283

    Open questions at the time
    • Upstream signals controlling Nedd4-2 activity on this channel not defined
    • Phosphorylation state of TPVT motif in vivo not measured
  16. 2019 High

    Established the central physiological circuit: Kir4.1/Kir5.1 is the DCT sensor that translates dietary Na+ and K+ into membrane potential changes that set NCC activity, with Kir5.1 required for both Na+- and K+-sensing.

    Evidence Kir5.1 and kidney-specific Kir4.1 knockout mice with patch-clamp, immunoblotting, and renal clearance under varied diets

    PMID:30559144 PMID:31239388

    Open questions at the time
    • Molecular link from membrane potential to WNK-SPAK-NCC cascade not fully resolved here
    • Relative weighting of K+ versus Na+ signals unclear
  17. 2019 High

    Identified hormonal (β-adrenergic/PKA) activation of the DCT channel as an NCC-regulatory input and demonstrated whole-animal chemoreflex deficits, broadening Kir5.1's physiological reach to blood pressure and respiratory control.

    Evidence DCT patch-clamp with PKA pharmacology and Kir4.1-KO mice; plethysmography and blood gas in Kcnj16-KO rats

    PMID:30571558 PMID:30605394

    Open questions at the time
    • PKA phosphorylation target on the channel not mapped in vivo
    • Integration of renal and respiratory phenotypes incomplete
  18. 2020 High

    Confirmed by double-knockout epistasis that Nedd4-2 regulates NCC partly through Kir4.1/Kir5.1, integrating ubiquitin-mediated control into the salt-handling circuit.

    Evidence Kidney-specific Nedd4-2 KO, Kir4.1 KO, and double-KO mice with electrophysiology and biochemistry

    PMID:32295826

    Open questions at the time
    • Nedd4-2 effects on NCC independent of the channel not fully quantified
  19. 2021 High

    Extended the channel's roles to neuronal excitability and reproduction, and—critically—established KCNJ16 mutations as the cause of a human tubulopathy with deafness through loss of heteromeric channel function.

    Evidence Kcnj16-KO rat EEG/seizure and KO-mouse fertility studies; human whole-exome sequencing with oocyte functional assays of patient mutations

    PMID:33232300 PMID:33811157 PMID:34205849

    Open questions at the time
    • Cellular site of Kir5.1 action in seizures and sperm not defined
    • Genotype-phenotype correlation across patient mutations incomplete
  20. 2021 High

    Resolved a novel intrinsic, cation-independent inward rectification mechanism driven by voltage-dependent K+-flux gating, refining the biophysical model of the heteromer.

    Evidence Excised inside-out patch-clamp in HEK cells with removal of blocking cations, PIP2, and mutagenesis

    PMID:33822868

    Open questions at the time
    • Structural gate underlying flux-dependent gating not identified
  21. 2023 Medium

    Added calcineurin/PP2B (via FKBP-12/Src) and CaSR-PLC-PKC as regulatory inputs and revealed an N6amt1/m6A epigenetic pathway controlling Kcnj16 in neuropathic pain, expanding the regulatory and pathophysiological repertoire.

    Evidence DCT patch-clamp with FK506/CsA and FKBP-12/Kir4.1 KO mice; spinal nerve ligation model with N6amt1 manipulation and promoter m6A analysis

    PMID:36821372 PMID:37624905

    Open questions at the time
    • Direct molecular target of PP2B on the channel not identified
    • m6A/Kcnj16 pain mechanism from single lab
  22. 2025 High

    Demonstrated that Kir5.1 is required for assembly and basolateral targeting of the proximal-tubule Kir4.2/Kir5.1 50-pS channel and dissected the temporal dependence of angiotensin-II NCC stimulation on the channel.

    Evidence Kir5.1-KO mice with single-channel patch-clamp and membrane potential recording; AT1aR-KO and Kir4.1-KO mice with WNK4/SPAK/NCC phosphorylation epistasis

    PMID:39745541 PMID:40241495

    Open questions at the time
    • Mechanism of the long-term, channel-independent Ang-II effect on NCC unknown
    • Proximal-tubule physiological consequences of channel loss incompletely defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution structure of the Kir4.x/Kir5.1 heteromer and the precise molecular path from basolateral membrane potential to WNK-SPAK-NCC phosphorylation remain to be defined.
  • No experimental structure of the heteromeric channel
  • Membrane-potential-to-WNK signaling step not molecularly resolved
  • Cellular substrate of seizure and fertility phenotypes unmapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005215 transporter activity 4 GO:0140299 molecular sensor activity 3 GO:0008289 lipid binding 2
Localization
GO:0005886 plasma membrane 5 GO:0005829 cytosol 3
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-382551 Transport of small molecules 4 R-HSA-112316 Neuronal System 2
Partners
KCNJ10KCNJ15NEDD4LPSD-95SYNTROPHIN
Complex memberships
Kir4.1/Kir5.1 heterotetramerKir4.2/Kir5.1 heterotetramer

Evidence

Reading pass · 35 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 Kir5.1 (KCNJ16) does not form functional homomeric channels; it requires co-expression with Kir4.1 to produce functional heteromeric channels, and the Kir5.1 subunit confers extreme sensitivity to inhibition by intracellular acidification on the Kir5.1/Kir4.1 heteromer—a property not present in homomeric Kir4.1. Heterologous expression in Xenopus oocytes with two-electrode voltage clamp; Kir5.1-specific antibodies for localization in renal tubular epithelia The Journal of biological chemistry High 10764726
2000 Hypercapnia inhibits Kir4.1-Kir5.1 heteromeric currents via intracellular acidification (not molecular CO2 directly); co-expression of Kir5.1 with Kir4.1 shifts the pKa from ~6.03 (homomeric Kir4.1) to ~7.45 (heteromeric Kir4.1-Kir5.1), placing it within the physiological pH range. A lysine residue at position 67 in the N-terminus of Kir4.1 (K67M mutation) completely eliminates CO2 sensitivity of both homomeric Kir4.1 and heteromeric Kir4.1-Kir5.1. Two-electrode voltage clamp and excised inside-out patches in Xenopus oocytes; site-directed mutagenesis (K67M) The Journal of physiology High 10790154 10871638
2000 Heteromeric Kir4.1-Kir5.1 channels have a single-channel conductance of ~59 pS and open probability ~0.4 at pH 7.4; low pH selectively suppresses open-state probability without affecting single-channel conductance. PIP2 enhances baseline open probability and reduces pH sensitivity (shifts pKa from 7.45 to 7.22) of Kir4.1-Kir5.1 but not homomeric Kir4.1; this PIP2 effect requires Arg178 in Kir5.1. Inside-out patch-clamp in Xenopus oocytes; exogenous PIP2 application; site-directed mutagenesis (R178 in Kir5.1, K67M/Q in Kir4.1) The Journal of general physiology High 10871638
2001 Kir5.1 forms functional heteromeric channels with Kir4.2 (not only Kir4.1); Kir4.2 has a much higher intrinsic pH sensitivity (pKa ~7.1) than Kir4.1 (pKa ~5.99) due to a C-terminal mechanism, so co-expression with Kir5.1 does not cause a major pKa shift for Kir4.2-Kir5.1. However, Kir5.1 converts Kir4.2 from a high-open-probability (~0.9) channel into novel bursting channels (open probability <0.3) and increases single-channel conductance from ~25 pS to ~54 pS. Heterologous expression in Xenopus oocytes; cell-attached single-channel recording; pH titration experiments The Journal of physiology High 11306656
2001 Kir5.1, when co-expressed with Kir2.1, forms electrically silent heteromeric channels, thereby negatively suppressing Kir2.1 channel activity in native cells. Kir5.1 is efficiently targeted to the cell surface in Xenopus oocytes but forms silent channels with Kir2.1. Expression in Xenopus oocytes; electrophysiology; chromosomal mapping; in situ hybridization FEBS letters Medium 11240146
2002 PSD-95 enables homomeric Kir5.1 channels to reach the plasma membrane and become functional: without PSD-95, Kir5.1 distributes mostly in the cytoplasm due to rapid internalization; with PSD-95 co-expression, Kir5.1 clusters on the plasma membrane and produces Ba2+-sensitive inwardly rectifying K+ currents. PKA-mediated phosphorylation of the Kir5.1 C-terminus prevents PSD-95 binding and promptly suppresses these currents. Co-transfection in HEK293T cells; electrophysiology; immunofluorescence; co-immunoprecipitation from brain tissue; PKA activation/inhibition Neuron High 11988170
2002 Kir5.1 exhibits highly selective heteromultimerization: it physically associates with members of the Kir4.0 subfamily (Kir4.1, Kir4.2) but does not physically associate with Kir1.1, Kir2.1, or Kir6.2. Specific regions within the Kir4.1 subunit govern the selectivity of this interaction. Co-immunoprecipitation and functional expression in Xenopus oocytes; deletion/chimera mutagenesis of Kir subunits American journal of physiology. Cell physiology Medium 12456399
2003 Residues at an intersubunit interface between the cytoplasmic domains of Kir5.1 and Kir4.1 are critical for the novel rectification, gating properties, and pH sensitivity of heteromeric Kir4.1/Kir5.1 channels, providing a structural mechanism for functional coupling of these properties in heteromeric channels. Site-directed mutagenesis combined with whole-cell and excised-patch electrophysiology in Xenopus oocytes The Journal of biological chemistry High 12923169
2004 In mouse brain, Kir5.1 assembles differentially with Kir4.1 in a region-specific fashion: heteromeric Kir4.1/Kir5.1 is present in neocortex and olfactory bulb glomeruli, while homomeric Kir4.1 predominates in hippocampus and thalamus. Both channel types are expressed exclusively in astrocytes at membranes facing pia mater, blood vessels, and synaptic processes, and both associate with PDZ domain-containing syntrophins, implicated in subcellular targeting. Immunoprecipitation from mouse brain; immunolabeling with subunit-specific antibodies; co-immunoprecipitation with syntrophins The Journal of biological chemistry High 15310750
2004 In the cochlear lateral wall, Kir5.1 is specifically expressed in type II, IV, and V fibrocytes of the spiral ligament (directly involved in K+ circulation), whereas Kir4.1 is exclusively in the stria vascularis—demonstrating that the two subunits occupy distinct regions and do not co-assemble in the cochlea, unlike in renal epithelia or retinal Müller cells. Immunohistochemistry with subunit-specific antibodies; double-immunolabeling; developmental expression analysis The European journal of neuroscience Medium 14750965
2007 Heteromeric Kir4.1-Kir5.1 (but not homomeric Kir4.1) is strongly inhibited by PKC activation via reduction of open probability; this inhibition is independent of PIP2 depletion and PKC-dependent internalization. Multiple potential PKC phosphorylation sites exist in both Kir4.1 and Kir5.1 C-terminal peptides (phosphorylated in vitro), but individual site mutagenesis failed to abolish the effect, suggesting redundancy. Tandem dimer Kir4.1-Kir5.1 expressed in Xenopus oocytes; PMA (PKC activator) and specific PKC inhibitors; single-channel recordings; in vitro phosphorylation; site-directed mutagenesis Biochimica et biophysica acta Medium 17585871
2008 Heteromeric Kir4.1-Kir5.1 is inhibited by serotonin (5-HT), substance-P, and thyrotropin-releasing hormone specifically through Gαq-protein-coupled receptors and downstream PKC activation; homomeric Kir4.1 is unaffected by these neurotransmitters. CO2/pH sensitivity of Kir4.1-Kir5.1 is preserved after neurotransmitter-induced inhibition. Xenopus oocyte expression; two-electrode voltage clamp; receptor pharmacology; PKC inhibitors; immunostaining in brainstem neurons Journal of cellular physiology Medium 17559083
2008 Kir4.1/Kir5.1 heterotetramer forms the predominant basolateral K+ channel (40 pS) in mouse cortical collecting duct principal cells, confirmed by co-localization of both subunit proteins with aquaporin-2 (principal cell marker) but absence from intercalated cells; channel activity is pH-sensitive with pK of 7.24 and is upregulated by Na+-depleted diet. Patch-clamp (cell-attached and inside-out), real-time PCR, immunohistochemistry, dietary manipulation American journal of physiology. Renal physiology High 18367659
2010 Genetic deletion of Kcnj16 (Kir5.1) in mice dramatically reduces and delays the response of locus coeruleus neurons to cytoplasmic alkalinization and acidification, identifying Kir5.1 as a required determinant of PCO2/pH sensitivity in locus coeruleus neurons. Kcnj16 knockout mice; patch-clamp electrophysiology of locus coeruleus neurons in brain slices; pH manipulation The Journal of biological chemistry High 21047793
2011 Disruption of Kcnj16 (Kir5.1) in mice causes hypokalemic, hyperchloremic metabolic acidosis with hypercalciuria and exaggerated response to hydrochlorothiazide, indicating excessive Na+ absorption in the DCT. Loss of Kir5.1 abolishes pH sensitivity of basolateral K+ conductance in the DCT (remaining homomeric Kir4.1 has reduced pH sensitivity), establishing Kir5.1 as a pH-sensitive regulator of salt transport in the DCT. Targeted gene disruption (Kcnj16-/- mice); metabolic cage studies; patch-clamp electrophysiology of DCT basolateral membrane; pharmacological challenge (hydrochlorothiazide) Proceedings of the National Academy of Sciences of the United States of America High 21633011
2012 S-glutathionylation of Cys158 in the TM2 helix of Kir5.1 is the mechanism by which oxidative stress (H2O2, diamide+GSH, GSSG) inhibits heteromeric Kir4.1-Kir5.1 but not homomeric Kir4.1. A single glutathione moiety at Cys158 is sufficient to block the channel; the modification is state-dependent (requires open channel) and accessible only to intracellular oxidants. HEK cell expression; whole-cell and inside-out patch-clamp; site-directed mutagenesis (C158A, C158T); tandem dimer constructs; biochemical GSH interaction assay The Journal of physiology High 22907060
2013 Co-expression of KCNJ16 (Kir5.1) with the KCNJ10 (Kir4.1) p.A167V mutation in Xenopus oocytes almost completely abolishes heteromeric channel function, even though the p.A167V mutation alone retains large residual function as a homomeric channel—demonstrating that Kir5.1 can suppress a gain-of-function mutation and that in vitro assessment of KCNJ10 mutations may require co-expression with KCNJ16. Heterologous expression in Xenopus oocytes; two-electrode voltage clamp; Ba2+ inhibition assay; Western blot Nephron. Physiology Medium 24193250
2017 HNF1β directly transcriptionally activates Kcnj16 (Kir5.1): a conserved HNF1β-binding site in the Kcnj16 promoter drives 2.2-fold increased luciferase reporter expression; a disease-causing HNF1β mutant (p.Lys156Glu) fails to activate Kcnj16 expression; Hnf1β knockdown in mpkDCT cells reduces Kcnj16 by 38%, and renal HNF1β knockout mice show 78% reduction in Kcnj16 transcript. ChIP-seq; luciferase promoter assay; siRNA knockdown; HNF1β renal knockout mouse; qPCR Kidney international High 28577853
2017 Kcnj16 knockout in Dahl salt-sensitive rats (SSKcnj16-/-) causes hypokalemia and reduced blood pressure; high-salt diet causes 100% mortality from salt wasting and severe hypokalemia. In knockout rats, Kir4.1 is upregulated but predominantly localizes to the cytosol rather than basolateral membrane. Benzamil (ENaC blocker) rescues mortality, while hydrochlorothiazide and furosemide do not, placing Kir5.1 upstream of ENaC-dependent Na+ transport in this context. Kcnj16 knockout rat (genetic deletion); electrophysiology of collecting duct; immunohistochemistry; dietary challenges; pharmacological rescue experiments JCI insight High 28931751
2018 Nedd4-2 binds to the phosphothreonine motif (TPVT, AA249-252) in the C-terminus of Kir5.1, and this interaction facilitates ubiquitination of Kir4.1 in the Kir4.1/Kir5.1 heterotetramer—reducing Kir4.1 membrane expression and K+ current. Nedd4-2 does not affect Kir4.1 in the absence of Kir5.1, and the Kir5.1 T249A mutation abolishes Nedd4-2 association and its inhibitory effect. Co-immunoprecipitation; GST pulldown; ubiquitination assay; patch-clamp; Western blot; site-directed mutagenesis (T249A); kidney-specific Nedd4-2 knockout mice American journal of physiology. Renal physiology High 29897283
2018 Kir4.1/Kir5.1 activity in the DCT is essential for dietary sodium intake to regulate NCC: low sodium intake stimulates basolateral Kir4.1/Kir5.1, hyperpolarizes the DCT membrane, and upregulates NCC; high sodium intake has opposite effects. Kidney-specific Kir4.1 knockout abolishes the effect of dietary sodium intake on NCC activity, placing Kir4.1/Kir5.1 upstream of NCC in this regulatory pathway. Patch-clamp electrophysiology; immunoblotting; renal clearance; kidney-specific Kir4.1 knockout mice; dietary manipulation Journal of the American Society of Nephrology : JASN High 30559144
2019 Deletion of Kir5.1 abolishes the ability of dietary K+ intake to modulate basolateral DCT K+ conductance, DCT membrane potential, and NCC expression/activity; Kir5.1 KO mice cannot appropriately excrete K+ during high-K+ intake or conserve K+ during restriction, establishing Kir5.1 as essential for dietary K+-sensing regulation of NCC and K+ homeostasis. Kir5.1 knockout mice (Kcnj16-/-); patch-clamp electrophysiology; renal clearance; immunoblotting; high/low/normal K+ diets Journal of the American Society of Nephrology : JASN High 31239388
2019 Norepinephrine stimulates basolateral Kir4.1/Kir5.1 (40 pS channel) in the DCT via β-adrenergic receptor → cAMP → PKA signaling pathway; this activation hyperpolarizes the DCT membrane and is required for norepinephrine-induced upregulation of NCC, as the effect on NCC is absent in kidney-specific Kir4.1 knockout mice. Patch-clamp electrophysiology; pharmacological dissection (PKA inhibitors, isoproterenol, propranolol); immunoblotting; renal clearance; kidney-specific Kir4.1 KO mice Hypertension High 30571558
2019 Kcnj16 mutation in Dahl SS rats blunts the ventilatory response to graded hypercapnic acidosis by up to 45% and nearly abolishes the hypoxic ventilatory response, establishing Kir5.1 as a key regulator of renal H+ handling and CO2/O2 chemoreflexes. Kcnj16 knockout Dahl SS rat; whole-body plethysmography; arterial blood gas measurement; pharmacological interventions (bicarbonate, hydrochlorothiazide, high-K+ diet) FASEB journal High 30605394
2020 Kidney-specific Nedd4-2 deletion increases Kir4.1/Kir5.1 activity and Kir4.1 membrane expression in the DCT, hyperpolarizes DCT membrane, and increases NCC expression/activity; double knockout of Nedd4-2 and Kir4.1 abolishes Nedd4-2 effects on K+ conductance and NCC, confirming that Nedd4-2 regulates NCC partly through Kir4.1/Kir5.1. Kidney-specific knockout mice (Nedd4-2 KO, Kir4.1 KO, double KO); electrophysiology; immunoblotting; immunostaining; renal clearance Journal of the American Society of Nephrology : JASN High 32295826
2021 Kcnj16 knockout in Dahl SS rats causes audiogenic seizures (sound-induced tonic-clonic seizures confirmed by EEG); repeated seizure induction worsens hypokalemia and causes ~38% mortality in males. Dietary K+ supplementation mitigated hypokalemia and prevented seizure-related mortality but did not prevent seizures, identifying a non-redundant role for Kir5.1 in neuronal excitability control. Kcnj16 knockout rat; EEG recording; dietary K+ supplementation; behavioral testing JCI insight High 33232300
2021 Mutations in KCNJ16 cause a novel human tubulopathy (hypokalemia, salt wasting, disturbed acid-base homeostasis, sensorineural deafness); co-expression of mutant KCNJ16 with KCNJ15 or KCNJ10 in Xenopus oocytes significantly reduces K+ currents, demonstrating that loss-of-function of heteromeric channels underlies the disease. Whole-exome sequencing; heterologous expression in Xenopus oocytes; two-electrode voltage clamp; surface expression assays Journal of the American Society of Nephrology : JASN High 33811157
2021 Deletion of Kir5.1 abolishes the inhibitory effect of high Na+ intake on basolateral Kir4.1/Kir5.1 and NCC expression/activity in DCT, and prevents low-Na+-induced stimulation of these channels, demonstrating that Kir5.1 is required for dietary Na+-sensing regulation of NCC. Kir5.1 knockout mice; patch-clamp; immunoblotting; renal clearance; dietary Na+ manipulation American journal of physiology. Renal physiology High 33900854
2021 Kcnj16 gene ablation in mice causes subfertility: 20% of Kir5.1 KO male mice are infertile, 50% of males >3 months cannot breed, testes are smaller, and a greater proportion of sperm display folded flagella (abnormal morphology). Kir5.1 is expressed in spermatozoa (Kir4.1 expressed in epididymal duct smooth muscle/epithelial cells), identifying Kir5.1 as important for sperm flagellar morphology and fertility. Kcnj16 knockout mice; fertility testing; histology; immunohistochemistry; sperm motility analysis International journal of molecular sciences Medium 34205849
2021 Kir4.1/Kir5.1 heteromeric channels exhibit a novel intrinsic inward rectification mechanism in the absence of blocking cations (polyamines, Mg2+), generated by voltage-dependent K+-flux gating: inward K+ flux opens the gate, while outward flux cannot maintain the gate open. Saturating PIP2 greatly reduces this intrinsic rectification. HEK cell expression; excised inside-out patch-clamp; pharmacological removal of blocking cations; PIP2 application; site-directed mutagenesis The Journal of general physiology High 33822868
2023 Inhibition of calcineurin/PP2B by tacrolimus (FK506) or cyclosporine A stimulates Kir4.1/Kir5.1 in the DCT and upregulates NCC; FK506 effects require FKBP-12 (absent in FKBP-12 KO) while CsA does not, both pointing to PP2B inhibition as the mechanism. Src family protein tyrosine kinase activity is required for the stimulatory effect, and the effect on NCC is Kir4.1-dependent. Patch-clamp; immunoblotting; immunofluorescence; kidney-specific FKBP-12 KO and Kir4.1 KO mice; pharmacological dissection (SFK inhibitor, H2O2) JCI insight High 36821372
2023 Peripheral nerve injury decreases N6amt1 (DNA N6-methyladenine methyltransferase) in dorsal horn neurons, reducing m6A methylation at the Kcnj16 promoter, which upregulates Kcnj16 expression in the dorsal horn and contributes to neuropathic pain. Restoring N6amt1 reverses Kcnj16 upregulation and alleviates pain hypersensitivity; mimicking N6amt1 downregulation in naive mice elevates Kcnj16 and produces neuropathic pain-like behaviors. Spinal nerve ligation model; N6amt1 rescue (viral overexpression); m6A methylation analysis at Kcnj16 promoter; behavioral pain assays; N6amt1 knockdown in naive mice Pain Medium 37624905
2025 Kir5.1 is essential for assembly of the basolateral 50-pS K+ channel (Kir4.2/Kir5.1 heterotetramer) in the proximal tubule: the 50-pS channel is completely absent in Kir5.1 KO mice, and Kir4.2 expression and basolateral membrane staining are significantly reduced (while Kir4.1 in DCT is increased), resulting in depolarization of the proximal tubule membrane potential. Kir5.1 knockout mice; single-channel patch-clamp; immunoblotting; immunofluorescence; membrane potential recording American journal of physiology. Renal physiology High 39745541
2025 Short-term (1-day) angiotensin-II-induced stimulation of NCC (via WNK4 and SPAK phosphorylation) depends on Kir4.1/Kir5.1 activity, as this effect is abolished in kidney-specific Kir4.1 KO mice. However, long-term (7-day) Ang-II can stimulate NCC by a Kir4.1/Kir5.1-independent mechanism. Kidney-specific AT1aR KO and Kir4.1 KO mice; patch-clamp; immunoblotting (pWNK4, pSPAK, pNCC, tNCC); renal clearance with thiazide American journal of physiology. Renal physiology High 40241495
2026 Activation of basolateral calcium-sensing receptor (CaSR) in the DCT inhibits Kir4.1/Kir5.1 and depolarizes the DCT membrane via PLC-PKC pathway; CaSR agonist R-568 effect is abolished by PLC or PKC inhibitors, and elevated extracellular Ca2+ (5 mM) similarly inhibits the channel by a PKC-dependent mechanism. Cell-attached patch-clamp in isolated DCT; CaSR agonists (R-568, neomycin); PLC inhibitor; PKC inhibitor (calphostin-C); Ca2+ manipulation American journal of physiology. Renal physiology Medium 41886268

Source papers

Stage 0 corpus · 72 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Differential assembly of inwardly rectifying K+ channel subunits, Kir4.1 and Kir5.1, in brain astrocytes. The Journal of biological chemistry 142 15310750
2002 An inward rectifier K(+) channel at the basolateral membrane of the mouse distal convoluted tubule: similarities with Kir4-Kir5.1 heteromeric channels. The Journal of physiology 138 11790808
2010 Astrocytes in the retrotrapezoid nucleus sense H+ by inhibition of a Kir4.1-Kir5.1-like current and may contribute to chemoreception by a purinergic mechanism. Journal of neurophysiology 123 20926613
2001 Differential pH sensitivity of Kir4.1 and Kir4.2 potassium channels and their modulation by heteropolymerisation with Kir5.1. The Journal of physiology 120 11306656
2000 pH dependence of the inwardly rectifying potassium channel, Kir5.1, and localization in renal tubular epithelia. The Journal of biological chemistry 113 10764726
2000 Modulation of kir4.1 and kir5.1 by hypercapnia and intracellular acidosis. The Journal of physiology 110 10790154
2008 Kir4.1/Kir5.1 channel forms the major K+ channel in the basolateral membrane of mouse renal collecting duct principal cells. American journal of physiology. Renal physiology 103 18367659
2000 Biophysical and molecular mechanisms underlying the modulation of heteromeric Kir4.1-Kir5.1 channels by CO2 and pH. The Journal of general physiology 95 10871638
2011 Renal phenotype in mice lacking the Kir5.1 (Kcnj16) K+ channel subunit contrasts with that observed in SeSAME/EAST syndrome. Proceedings of the National Academy of Sciences of the United States of America 91 21633011
2017 Essential role of Kir5.1 channels in renal salt handling and blood pressure control. JCI insight 85 28931751
2003 Differential expression and distribution of Kir5.1 and Kir4.1 inwardly rectifying K+ channels in retina. American journal of physiology. Cell physiology 64 12686518
2004 Expression of an inwardly rectifying K+ channel, Kir5.1, in specific types of fibrocytes in the cochlear lateral wall suggests its functional importance in the establishment of endocochlear potential. The European journal of neuroscience 60 14750965
2016 Expression of Kir4.1 and Kir5.1 inwardly rectifying potassium channels in oligodendrocytes, the myelinating cells of the CNS. Brain structure & function 58 26879293
2002 PSD-95 mediates formation of a functional homomeric Kir5.1 channel in the brain. Neuron 58 11988170
2021 Defects in KCNJ16 Cause a Novel Tubulopathy with Hypokalemia, Salt Wasting, Disturbed Acid-Base Homeostasis, and Sensorineural Deafness. Journal of the American Society of Nephrology : JASN 56 33811157
2001 Genetic and functional linkage of Kir5.1 and Kir2.1 channel subunits. FEBS letters 51 11240146
2019 Kir4.1/Kir5.1 in the DCT plays a role in the regulation of renal K+ excretion. American journal of physiology. Renal physiology 49 30623727
2019 Deletion of Kir5.1 Impairs Renal Ability to Excrete Potassium during Increased Dietary Potassium Intake. Journal of the American Society of Nephrology : JASN 47 31239388
2003 Identification of a heteromeric interaction that influences the rectification, gating, and pH sensitivity of Kir4.1/Kir5.1 potassium channels. The Journal of biological chemistry 47 12923169
2010 Genetic inactivation of Kcnj16 identifies Kir5.1 as an important determinant of neuronal PCO2/pH sensitivity. The Journal of biological chemistry 45 21047793
2017 Loss of transcriptional activation of the potassium channel Kir5.1 by HNF1β drives autosomal dominant tubulointerstitial kidney disease. Kidney international 38 28577853
2013 KCNJ10 mutations display differential sensitivity to heteromerisation with KCNJ16. Nephron. Physiology 36 24193250
2021 Deletion of Kcnj16 in Mice Does Not Alter Auditory Function. Frontiers in cell and developmental biology 35 33693002
2018 Kir4.1/Kir5.1 Activity Is Essential for Dietary Sodium Intake-Induced Modulation of Na-Cl Cotransporter. Journal of the American Society of Nephrology : JASN 33 30559144
2018 Kir5.1 regulates Nedd4-2-mediated ubiquitination of Kir4.1 in distal nephron. American journal of physiology. Renal physiology 30 29897283
2009 Modulation of Kir4.1 and Kir4.1-Kir5.1 channels by small changes in cell volume. Neuroscience letters 26 19429167
2002 Identification of domains that control the heteromeric assembly of Kir5.1/Kir4.0 potassium channels. American journal of physiology. Cell physiology 24 12456399
2001 Modulation of the heteromeric Kir4.1-Kir5.1 channels by P(CO(2)) at physiological levels. Journal of cellular physiology 24 11598908
2019 Norepinephrine-Induced Stimulation of Kir4.1/Kir5.1 Is Required for the Activation of NaCl Transporter in Distal Convoluted Tubule. Hypertension (Dallas, Tex. : 1979) 23 30571558
2020 Renal Tubule Nedd4-2 Deficiency Stimulates Kir4.1/Kir5.1 and Thiazide-Sensitive NaCl Cotransporter in Distal Convoluted Tubule. Journal of the American Society of Nephrology : JASN 22 32295826
2019 Genetic mutation of Kcnj16 identifies Kir5.1-containing channels as key regulators of acute and chronic pH homeostasis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 21 30605394
2000 The human inward rectifier K(+) channel subunit kir5.1 (KCNJ16) maps to chromosome 17q25 and is expressed in kidney and pancreas. Cytogenetics and cell genetics 21 11060447
2022 Inwardly rectifying K+ channels 4.1 and 5.1 (Kir4.1/Kir5.1) in the renal distal nephron. American journal of physiology. Cell physiology 20 35759440
2007 Protein kinase C dependent inhibition of the heteromeric Kir4.1-Kir5.1 channel. Biochimica et biophysica acta 20 17585871
2021 Kcnj16 knockout produces audiogenic seizures in the Dahl salt-sensitive rat. JCI insight 19 33232300
2019 Relationship between the renin-angiotensin-aldosterone system and renal Kir5.1 channels. Clinical science (London, England : 1979) 17 31799617
2022 EAST/SeSAME Syndrome and Beyond: The Spectrum of Kir4.1- and Kir5.1-Associated Channelopathies. Frontiers in physiology 16 35370765
2022 lncRNA XIST is associated with preeclampsia and mediates trophoblast cell invasion via miR-340-5p/KCNJ16 signaling pathway. Transplant immunology 15 35809813
2021 Deletion of Kir5.1 abolishes the effect of high Na+ intake on Kir4.1 and Na+-Cl- cotransporter. American journal of physiology. Renal physiology 15 33900854
2012 S-Glutathionylation underscores the modulation of the heteromeric Kir4.1-Kir5.1 channel in oxidative stress. The Journal of physiology 15 22907060
2022 Kir5.1 channels: potential role in epilepsy and seizure disorders. American journal of physiology. Cell physiology 12 35848616
2015 Variability in a three-generation family with Pierre Robin sequence, acampomelic campomelic dysplasia, and intellectual disability due to a novel ∼1 Mb deletion upstream of SOX9, and including KCNJ2 and KCNJ16. Birth defects research. Part A, Clinical and molecular teratology 12 26663529
2022 Role of inwardly rectifying K+ channel 5.1 (Kir5.1) in the regulation of renal membrane transport. Current opinion in nephrology and hypertension 11 35894283
2017 Identifying Candidate Genes that Underlie Cellular pH Sensitivity in Serotonin Neurons Using Transcriptomics: A Potential Role for Kir5.1 Channels. Frontiers in cellular neuroscience 11 28270749
2008 Modulation of the heteromeric Kir4.1-Kir5.1 channel by multiple neurotransmitters via Galphaq-coupled receptors. Journal of cellular physiology 11 17559083
2023 Calcineurin inhibitors stimulate Kir4.1/Kir5.1 of the distal convoluted tubule to increase NaCl cotransporter. JCI insight 10 36821372
2021 Deletion of renal Nedd4-2 abolishes the effect of high K+ intake on Kir4.1/Kir5.1 and NCC activity in the distal convoluted tubule. American journal of physiology. Renal physiology 10 34029145
2023 Activation of Kir4.1/Kir5.1 contributes to the cyclosporin A-induced stimulation of the renal NaCl cotransporter and hyperkalemic hypertension. Acta physiologica (Oxford, England) 9 36764674
2006 Modulation of Kir4.2 rectification properties and pHi-sensitive run-down by association with Kir5.1. Biochimica et biophysica acta 9 16949552
2023 Diverse functions of the inward-rectifying potassium channel Kir5.1 and its relationship with human diseases. Frontiers in physiology 8 36923292
2023 Repeated seizures lead to progressive ventilatory dysfunction in SS rats. Journal of applied physiology (Bethesda, Md. : 1985) 8 37535709
2021 Kcnj16 (Kir5.1) Gene Ablation Causes Subfertility and Increases the Prevalence of Morphologically Abnormal Spermatozoa. International journal of molecular sciences 7 34205849
2023 DNA N6-methyladenine methylase N6AMT1 controls neuropathic pain through epigenetically modifying Kcnj16 in dorsal horn neurons. Pain 5 37624905
2021 Kir4.1/Kir5.1 channels possess strong intrinsic inward rectification determined by a voltage-dependent K+-flux gating mechanism. The Journal of general physiology 5 33822868
2015 Molecular insights into the possible role of Kir4.1 and Kir5.1 in thyroid hormone biosynthesis. Hormone research in paediatrics 5 25612510
2024 KCNJ16-depleted kidney organoids recapitulate tubulopathy and lipid recovery upon statins treatment. Stem cell research & therapy 4 39183338
2024 Familial severe skeletal Class II malocclusion with gingival hyperplasia caused by a complex structural rearrangement at the KCNJ2-KCNJ16 locus. HGG advances 4 39257002
2024 Characterization of a novel variant in KCNJ16, encoding Kir5.1 channel. Physiological reports 4 39414394
2023 Novel KCNJ16 variants identified in a Chinese patient with hypokalemic metabolic acidosis. Molecular genetics & genomic medicine 4 37466410
2009 Modulation of Kir4.1 and Kir4.1-Kir5.1 channels by extracellular cations. Biochimica et biophysica acta 4 19616510
2020 Epoxyeicosatrienoic acid metabolites inhibit Kir4.1/Kir5.1 in the distal convoluted tubule. American journal of physiology. Renal physiology 3 32308018
2025 Kir5.1 regulates Kir4.2 expression and is a key component of the 50-pS inwardly rectifying potassium channel in basolateral membrane of mouse proximal tubules. American journal of physiology. Renal physiology 2 39745541
2022 The effect of high-dietary K+ (HK) on Kir4.1/Kir5.1 and ROMK in the distal convoluted tubule (DCT) is not affected by gender and Cl- content of the diet. Frontiers in physiology 2 36439248
2025 Kir4.1/Kir5.1 of distal convoluted tubule is required for short-term angiotensin-II-induced stimulation of Na-Cl cotransporter. American journal of physiology. Renal physiology 1 40241495
2024 Deletion of Kcnj16 altered transcriptomic and metabolomic profiles of Dahl salt-sensitive rats. iScience 1 39328933
2024 Role of Kir5.1 (Kcnj16) Channels in Regulating Renal Ammonia Metabolism during Metabolic Acidosis in Dahl Salt-Sensitive Rats. The American journal of pathology 1 39341364
2021 Inhibitory effect of tumor necrosis factor-α on the basolateral Kir4.1/Kir5.1 channels in the thick ascending limb during diabetes. Experimental and therapeutic medicine 1 34539838
2026 Stimulation of basolateral calcium-sensing receptor inhibits Kir4.1/Kir5.1 in the mouse distal convoluted tubule. American journal of physiology. Renal physiology 0 41886268
2026 The role of kir4.1/Kir5.1 in mediating the effect of angiotensin-II on Na-Cl-cotransporter. Current opinion in nephrology and hypertension 0 42261750
2025 Intracellular pH regulates the strength of the intrinsic inward rectification of Kir4.1/Kir5.1 channels. Pflugers Archiv : European journal of physiology 0 40133722
2024 Role of Kir4.1/Kir5.1 in mediating Angiotensin-II (Ang-II)-induced stimulation of thiazide-sensitive Na-Cl cotransporter. bioRxiv : the preprint server for biology 0 39211089
2018 [The function and regulation of basolateral Kir4.1 and Kir4.1/Kir5.1 in renal tubules]. Sheng li xue bao : [Acta physiologica Sinica] 0 30560268

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