Kir4.1 channels contribute to astrocyte CO2/H+-sensitivity and the drive to breathe

Cleary, Colin M ORCID: https://orcid.org/0000-0003-0305-1324, Browning, Jack L ORCID: https://orcid.org/0000-0002-3102-0667, Armbruster, Moritz ORCID: https://orcid.org/0000-0003-2341-513X, Sobrinho, Cleyton R ORCID: https://orcid.org/0000-0002-1472-7169, Strain, Monica L, Jahanbani, Sarvin, Soto-Perez, Jaseph, Hawkins, Virginia E ORCID: https://orcid.org/0000-0001-9505-6776, Dulla, Chris G, Olsen, Michelle L ORCID: https://orcid.org/0000-0003-1394-664X and Mulkey, Daniel K ORCID: https://orcid.org/0000-0002-7040-3927 (2024) Kir4.1 channels contribute to astrocyte CO2/H+-sensitivity and the drive to breathe. Communications Biology, 7 (1). 373. ISSN 2399-3642

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Abstract

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO2/H+, however, it is not clear how these cells detect changes in CO2/H+. Considering Kir4.1/5.1 channels are CO2/H+-sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO2/H+ sensor in RTN astrocytes. To address this, we show that RTN astrocytes express Kir4.1 and Kir5.1 transcripts. We also characterized respiratory function in astrocyte-specific inducible Kir4.1 knockout mice (Kir4.1 cKO); these mice breathe normally under room air conditions but show a blunted ventilatory response to high levels of CO2, which could be partly rescued by viral mediated re-expression of Kir4.1 in RTN astrocytes. At the cellular level, astrocytes in slices from astrocyte-specific inducible Kir4.1 knockout mice are less responsive to CO2/H+ and show a diminished capacity for paracrine modulation of respiratory neurons. These results suggest Kir4.1/5.1 channels in RTN astrocytes contribute to respiratory behavior.