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

• Published in: Communications biology Vol. 7; no. 1; pp. 373 - 13
• Main Authors: Cleary, Colin M., Browning, Jack L., Armbruster, Moritz, Sobrinho, Cleyton R., Strain, Monica L., Jahanbani, Sarvin, Soto-Perez, Jaseph, Hawkins, Virginia E., Dulla, Chris G., Olsen, Michelle L., Mulkey, Daniel K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 28-03-2024; Nature Publishing Group; Nature Portfolio
• Subjects: 14/19; 42/109; 42/34; 631/443/1784; 631/443/376; 9/74; Astrocytes; Biology; Biomedical and Life Sciences; Carbon dioxide; Genomics; Hydrogen; Insulin-like growth factors; Life Sciences; Neuromodulation; Neurosciences; Paracrine signalling; Physiology; Potassium channels (inwardly-rectifying); Proteins; Respiration; Respiratory function; Retrotrapezoid nucleus; Ventilatory behavior
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-024-06065-0

Astrocytes in the retrotrapezoid nucleus (RTN) stimulate breathing in response to CO
2
/H
+
, however, it is not clear how these cells detect changes in CO
2
/H
+
. Considering Kir4.1/5.1 channels are CO
2
/H
+
-sensitive and important for several astrocyte-dependent processes, we consider Kir4.1/5.1 a leading candidate CO
2
/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 CO
2
, 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 CO
2
/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.
Inducible deletion of Kir4.1 channels from astrocytes blunts the CO2/H + -dependent drive to breathe at the cellular and whole animal level in mice