Journal of Neurophysiology

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Astrocytes in the Retrotrapezoid Nucleus Sense H+ by Inhibition of a Kir4.1–Kir5.1-Like Current and May Contribute to Chemoreception by a Purinergic Mechanism

Ian C. Wenker, Orsolya Kréneisz, Akiko Nishiyama, Daniel K. Mulkey


Central chemoreception is the mechanism by which CO2/pH sensors regulate breathing in response to tissue pH changes. There is compelling evidence that pH-sensitive neurons in the retrotrapezoid nucleus (RTN) are important chemoreceptors. Evidence also indicates that CO2/H+-evoked adenosine 5′-triphosphate (ATP) release in the RTN, from pH-sensitive astrocytes, contributes to chemoreception. However, mechanism(s) by which RTN astrocytes sense pH is unknown and their contribution to chemoreception remains controversial. Here, we use the brain slice preparation and a combination of patch-clamp electrophysiology and immunohistochemistry to confirm that RTN astrocytes are pH sensitive and to determine mechanisms by which they sense pH. We show that pH-sensitive RTN glia are immunoreactive for aldehyde dehydrogenase 1L1, a marker of astrocytes. In HEPES buffer the pH-sensitive current expressed by RTN astrocytes reversed near EK+ (the equilibrium potential for K+) and was inhibited by Ba2+ and desipramine (blocker of Kir4.1-containing channels), characteristics most consistent with heteromeric Kir4.1–Kir5.1 channels. In bicarbonate buffer, the sodium/bicarbonate cotransporter also contributed to the CO2/H+-sensitive current in RTN astrocytes. To test the hypothesis that RTN astrocytes contribute to chemoreception by a purinergic mechanism, we used fluorocitrate to selectively depolarize astrocytes while measuring neuronal activity. We found that fluorocitrate increased baseline activity and pH sensitivity of RTN neurons by a P2-receptor–dependent mechanism, suggesting that astrocytes may release ATP to activate RTN chemoreceptors. We also found in bicarbonate but not HEPES buffer that P2-receptor antagonists decreased CO2 sensitivity of RTN neurons. We conclude that RTN astrocytes sense CO2/H+ in part by inhibition of a Kir4.1–Kir5.1-like current and may provide an excitatory purinergic drive to pH-sensitive neurons.


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