Regulation of breathing by CO ₂ requires the proton-activated receptor GPR4 in retrotrapezoid nucleus neurons

Abstract

Blood gas and tissue pH regulation depend on the ability of the brain to sense CO ₂ and/or H ⁺ and alter breathing appropriately, a homeostatic process called central respiratory chemosensitivity. We show that selective expression of the proton-activated receptor GPR4 in chemosensory neurons of the mouse retrotrapezoid nucleus (RTN) is required for CO ₂-stimulated breathing. Genetic deletion of GPR4 disrupted acidosis-dependent activation of RTN neurons, increased apnea frequency and blunted ventilatory responses to CO ₂. Reintroduction of GPR4 into RTN neurons restored CO ₂-dependent RTN neuronal activation and rescued the ventilatory phenotype. Additional elimination of TASK-2, a pH-sensitive K ⁺ channel expressed in RTN neurons, essentially abolished the ventilatory response to CO ₂. The data identify GPR4 and TASK-2 as distinct, parallel and essential central mediators of respiratory chemosensitivity.