Red blood cells protect oxygen transport with adrenergic sodium-proton exchangers in hypoxic and hypercapnic white seabass

White seabass (Atractoscion nobilis) are increasingly experiencing periods of low oxygen (O2; hypoxia) and high carbon dioxide (CO2, hypercapnia) due to climate change and eutrophication of the coastal waters of California. Haemoglobin (Hb) is the principal O2 carrier in the blood and in many teleost fishes Hb-O2 binding is compromised at low pH. However, Hb is contained within red blood cells (RBC) that, in some species, regulate intracellular pH with adrenergically-stimulated sodium-proton-exchangers ({beta}-NHE). We hypothesised that white seabass have RBC {beta}-NHEs that protect the blood O2-carrying capacity during hypoxia and hypercapnia. In a series of in vitro experiments, we determined the O2-binding characteristics of white seabass blood, the response of RBCs to adrenergic stimulation, and quantified the protective effect of {beta}-NHE activity on Hb-O2 saturation during a hypercapnic acidosis in normoxia and hypoxia. White seabass had typical teleost Hb characteristics, with a moderate O2 affinity that was highly pH-sensitive. Functional, molecular and bioinformatic data confirmed that white seabass have RBC {beta}-NHEs, and super-resolution imaging revealed, for the first time, the subcellular location of {beta}-NHE protein in intracellular vesicles and on the RBC membrane. The activation of RBC {beta}-NHEs increased Hb-O2 saturation by [~]8% in normoxia at 1% PCO2, and by [~]20% in hypoxia at arterial PCO2 (0.3%), but the protective effects decreased at higher PCO2. Combined, these data indicate that RBC {beta}-NHE activity in white seabass can safeguard arterial O2 transport and the mechanism likely plays an important role in the fishes physiological response to environmental hypoxia and hypercapnia. Summary StatementWhite seabass have highly pH-sensitive haemoglobins, but their red blood cells can actively protect oxygen transport during hypoxia and hypercapnia, conditions that occur more frequently due to a changing climate.