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 5HT₂ 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., PaO₂ = 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 O₂ and CO₂ with barometric pressure plethysmography after administering MSX-3 or ketanserin (A_2A and 5HT₂ 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.