Genetic inactivation of Kcnj16 identifies Kir5.1 as an important determinant of neuronal PCO₂/pH sensitivity

The molecular identity of ion channels which confer PCO₂/pH sensitivity in the brain is unclear. Heteromeric Kir4.1/Kir5.1 channels are highly sensitive to inhibition by intracellular pH and are widely expressed in several brainstem nuclei involved in cardiorespiratory control, including the locus coeruleus. This has therefore led to a proposed role for these channels in neuronal CO₂ chemosensitivity. To examine this, we generated mutant mice lacking the Kir5.1 (Kcnj16) gene. We show that although locus coeruleus neurons from Kcnj16^(+/+) mice rapidly respond to cytoplasmic alkalinization and acidification, those from Kcnj16^(-/-) mice display a dramatically reduced and delayed response. These results identify Kir5.1 as an important determinant of PCO₂/pH sensitivity in locus coeruleus neurons and suggest that Kir5.1 may be involved in the response to hypercapnic acidosis.