Serotonin and Adenosine G-protein Coupled Receptor Signaling for Ventilatory Acclimatization to Sustained Hypoxia

Different patterns of hypoxia evoke different forms of plasticity in the neural control of ventilation. For example, acute intermittent hypoxia produces long term facilitation (LTF) of ventilation, while chronic sustained hypoxia (CH) causes ventilatory acclimatization to hypoxia (VAH). In both LTF and VAH, ventilation in normoxia is greater than normal after the hypoxic stimulus is removed and the acute hypoxic ventilatory response can increase. However, the mechanisms of LTF and VAH are thought to be different based on previous results showing serotonin 5HT(2) receptors, which are G protein coupled receptors (GPCR) that activate G(Q) signaling, contribute to LTF but not VAH. Newer results show that a different GPCR, namely adenosine A(2A) receptors and the G(S) signaling pathway, cause LTF with more severe intermittent hypoxia, i.e., PaO(2) = 25–30 Torr for G(S) versus 35–45 Torr for LTF with the G(Q) signaling pathway. We hypothesized adenosine A(2A) receptors and G(S) signaling are involved in establishing VAH with longer term moderate CH and tested this in adult male rats by measuring ventilatory responses to O(2) and CO(2) with barometric pressure plethysmography after administering MSX-3 or ketanserin (A(2A) and 5HT(2) antagonists, respectively, both 1 mg/Kg i.p.) during CH for 7 days. Blocking G(S) or G(Q) signals throughout CH exposure, significantly decreased VAH. After VAH was established, G(Q) blockade did not affect ventilation while G(S) blockade increased VAH. Similar to LTF, data support roles for both G(Q) and G(S) pathways in the development of VAH but after VAH has been established, the G(S) pathway inhibits VAH.