Natasha N Kumar 1 , Ana Velic 2 , Jorge Soliz 3 , Yingtang Shi 1 , Keyong Li 1 , Sheng Wang 4 , Janelle L Weaver 1 , Josh Sen 1 , Stephen B G Abbott 5 , Roman M Lazarenko 1 , Marie-Gabrielle Ludwig 6 , Edward Perez-Reyes 1 , Nilufar Mohebbi 2 , Carla Bettoni 2 , Max Gassmann 7 , Thomas Suply 6 , Klaus Seuwen 6 , Patrice G Guyenet 1 , Carsten A Wagner 8 , Douglas A Bayliss 9
Jun 12 2015
Blood gas and tissue pH regulation depend on the ability of the brain to sense CO2 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 CO2-stimulated breathing. Genetic deletion of GPR4 disrupted acidosis-dependent activation of RTN neurons, increased apnea frequency, and blunted ventilatory responses to CO2. Reintroduction of GPR4 into RTN neurons restored CO2-dependent RTN neuronal activation and rescued the ventilatory phenotype. Additional elimination of TASK-2 (K(2P)5), a pH-sensitive K(+) channel expressed in RTN neurons, essentially abolished the ventilatory response to CO2. The data identify GPR4 and TASK-2 as distinct, parallel, and essential central mediators of respiratory chemosensitivity.