The importance of the pH-sensitive Kir5.1 channel in short-term and long-term regulation of pH

What is it about?

Maintenance of pH requires a complex, time-dependent integration of buffering mechanisms by the neural regulation of breathing and solute exchange in the kidney. pH-sensitive ion channels have long been thought to contribute to pH regulation, specifically through respiratory chemoreceptors - cells that are sensitive to pH and/or carbon dioxide (CO2) changes that drive changes in ventilation. Here we demonstrate in a rat with a mutation in the gene (kcnj16) encoding the inwardly-rectifying potassium channel 5.1 (Kir5.1; SSkcnj16-/- rats) both acute and chronic dysregulation of blood pH through disruption of renal and respiratory mechanisms. SSkcnj16-/- rats hyperventilated at rest in compensation for a chronic metabolic acidosis, and failed to respond to an acute respiratory acidosis. The normal coupling of arterial blood pH and CO2 levels to ventilation was also significantly blunted, and these ventilatory responses to hypercapnic acidosis were further reduced when chronic acidosis was corrected in treated SSkcnj16-/- rats. Ventilatory responses to hypoxia were also blunted in Kir5.1 mutant rats, indicating deficits in O2- and CO2-dependent mechanisms of respiratory chemoreception. While we previously showed increasing dietary potassium levels had previously improved cardiovascular dysfunction in SSkcnj16-/- rats, this treatment failed to correct pH regulation or other ventilatory phenotypes. These data demonstrate a direct and previously underappreciated role for Kir5.1 channels in acute (respiratory) and chronic (renal) pH regulation, suggesting that yet to be discovered mutations in kcnj16 in humans may contribute to complex syndromes involving pH/electrolyte imbalances and potential neural involvement.

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Why is it important?

This study shows the important function of a specific, pH-sensitive ion channel (Kir5.1) in the short-term and long-term regulation of body pH. This potassium ion channel binds to other Kir family subunits, conferring greater pH-sensitivity and increase single-channel conductance. However, the importance of this channel in global pH regulation has not been demonstrated. Here, we show that a mutation in the Kir5.1 gene (kcnj16) in rats leads to an inability to appropriately and acutely respond to hypercapnic acidosis, and dysfunction in renal mechanisms that act to buffer pH chronically. Partial correction of the chronic metabolic acidosis failed to improve, and instead exacerbated the blunted ventilatory sensitivity to hypercapnic acidosis, suggesting distinct but integrated roles for Kir5.1 in the neural control of breathing and kidney.