Ludwig, Marie-Gabrielle, Seuwen, Klaus and Suply, Thomas (2015) The proton-activated receptor GPR4 contributes to central respiratory chemosensitivity. Science.

Abstract

The ability to sense CO2/H+ is critical for normal breathing. A specific group of neurons within the medullary retrotrapezoid nucleus (RTN), identified by Phox2b-expression, are intrinsically sensitive to CO2/H+ and are preeminent central respiratory chemosensory neurons1,2. These excitatory neurons stimulate ventilation to rapidly regulate CO2 excretion and acid-base balance3 and they are selectively ablated in a mouse genetic model of human congenital central hypoventilation syndrome (CCHS) that recapitulates the blunted CO2-induced breathing and increased central apneas of CCHS4-6. However, the molecular mechanisms that mediate pH sensing in these neurons remain incompletely understood. Here, we demonstrate that GPR4, a proton-activated G protein-coupled receptor, represents a molecular substrate for CO2/H+-dependent regulation of RTN neuronal excitability and central respiratory chemosensitivity. Ventilatory stimulation by raised CO2, but not lowered O2, was strongly reduced in GPR4 knockout mice, which were also more prone to apneic events during quiet hyperoxic breathing. Mice lacking GPR4 showed a striking reduction in CO2 activation of RTN neurons in vivo, as determined by cFos expression. Likewise, RTN neuronal excitability and pH sensitivity in vitro were reduced by GPR4 deletion or receptor blockade, and modulated by intracellular application of GTP analogs. Finally, re-expression of GPR4 into RTN neurons of GPR4-/- mice rescued CO2-stimulated cFos expression and ventilation, and returned apneic frequencies to wild type levels. Taken together, this work identifies a new role for GPR4, defines a novel molecular component of central respiratory chemosensitivity, and suggests new therapeutic options to regulate breathing.

Item Type:	Article
Date Deposited:	13 Oct 2015 13:12
Last Modified:	13 Oct 2015 13:12
URI:	https://oak.novartis.com/id/eprint/22733