RGD Reference Report - Genetic mutation of Kcnj16 identifies Kir5.1-containing channels as key regulators of acute and chronic pH homeostasis. - Rat Genome Database

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Genetic mutation of Kcnj16 identifies Kir5.1-containing channels as key regulators of acute and chronic pH homeostasis.

Authors: Puissant, Madeleine M  Muere, Clarissa  Levchenko, Vladislav  Manis, Anna D  Martino, Paul  Forster, Hubert V  Palygin, Oleg  Staruschenko, Alexander  Hodges, Matthew R 
Citation: Puissant MM, etal., FASEB J. 2019 Apr;33(4):5067-5075. doi: 10.1096/fj.201802257R. Epub 2019 Jan 3.
RGD ID: 38500203
Pubmed: PMID:30605394   (View Abstract at PubMed)
PMCID: PMC6436665   (View Article at PubMed Central)
DOI: DOI:10.1096/fj.201802257R   (Journal Full-text)

Acute and chronic homeostatic pH regulation is critical for the maintenance of optimal cellular function. Renal mechanisms dominate global pH regulation over longer time frames, and rapid adjustments in ventilation compensate for acute pH and CO2 changes. Ventilatory CO2 and pH chemoreflexes are primarily determined by brain chemoreceptors with intrinsic pH sensitivity likely driven by K+ channels. Here, we studied acute and chronic pH regulation in Kcnj16 mutant Dahl salt-sensitive (SS Kcnj16-/-) rats; Kcnj16 encodes the pH-sensitive inwardly rectifying K+ 5.1 (Kir5.1) channel. SS Kcnj16-/- rats hyperventilated at rest, likely compensating for a chronic metabolic acidosis. Despite their resting hyperventilation, SS Kcnj16-/- rats showed up to 45% reduction in the ventilatory response to graded hypercapnic acidosis vs. controls. SS Kcnj16-/- rats chronically treated with bicarbonate or the carbonic anhydrase inhibitor hydrochlorothiazide had partial restoration of arterial pH, but there was a further reduction in the ventilatory response to hypercapnic acidosis. SS Kcnj16-/- rats also had a nearly absent hypoxic ventilatory response, suggesting major contributions of Kir5.1 to O2- and CO2-dependent chemoreflexes. Although previous studies demonstrated beneficial effects of a high-K+ diet (HKD) on cardiorenal phenotypes in SS Kcnj16-/- rats, HKD failed to restore the observed ventilatory phenotypes. We conclude that Kir5.1 is a key regulator of renal H+ handling and essential for acute and chronic regulation of arterial pH as determinants of the ventilatory CO2 chemoreflex.-Puissant, M. M., Muere, C., Levchenko, V., Manis, A. D., Martino, P., Forster, H. V., Palygin, O., Staruschenko, A., Hodges, M. R. Genetic mutation of Kcnj16 identifies Kir5.1-containing channels as key regulators of acute and chronic pH homeostasis.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
metabolic acidosis  ISOKcnj16 (Rattus norvegicus)38500203; 38500203compared to SS/JrHsdMcwiRGD 
metabolic acidosis  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
Respiratory Underresponsiveness to Hypoxia and Hypercapnia  ISOKcnj16 (Rattus norvegicus)38500203; 38500203compared to SS/JrHsdMcwiRGD 
Respiratory Underresponsiveness to Hypoxia and Hypercapnia  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
regulation of pH  IMP 38500203 RGD 
response to carbon dioxide  IMP 38500203 RGD 

Phenotype Annotations    Click to see Annotation Detail View

Mammalian Phenotype

TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
decreased circulating bicarbonate level  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
decreased circulating potassium level  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
hypercapnia  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
hyperventilation  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
increased circulating chloride level  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
metabolic acidosis  IMP 38500203; 38500203; 38500203compared to SS/JrHsdMcwiRGD 
Objects Annotated

Genes (Rattus norvegicus)
Kcnj16  (potassium inwardly-rectifying channel, subfamily J, member 16)
Kcnj16em1Mcwi  (potassium inwardly-rectifying channel, subfamily J, member 16; zinc finger nuclease induced mutant 1, Medical College of Wisconsin)

Genes (Mus musculus)
Kcnj16  (potassium inwardly-rectifying channel, subfamily J, member 16)

Genes (Homo sapiens)
KCNJ16  (potassium inwardly rectifying channel subfamily J member 16)

Strains
SS-Kcnj16em1Mcwi-/-  (NA)


Additional Information