New insights into urinary acidification and regulation of acid-base balance.

Systemic acid-base balance is primarily controlled by the renal excretion of acids and the exhalation of CO2 and both processes are tightly regulated and coordinated. Acid excretion into urine requires the formation of ammonium and its transport into urine as gaseous ammonia. Until recently it has been believed that NH3 would move across membranes by free diffusion according to Overton's rule. Recent structural, functional, and in vivo data show now that Rhesus proteins act as gas channels for NH3 and mediate renal acid excretion. Lack of the renal isoform RhCG in mice causes reduced ammonium excretion and metabolic acidosis. Breathing and exhalation of CO2 is stimulated and regulated by CO2 and acid sensors in the carotid bodies and the brain stem. GPR4 belongs to a small subfamily of G protein-coupled receptors and is activated by extracellular protons. Mice lacking GPR4 develop respiratory acidosis and are not able to increase ventilation appropriately in response to high CO2 levels or systemic acidosis. Thus, RhCG and GPR4 present novel paradigms of membrane proteins involved in controlling and regulating systemic acid-base balance in the major organs involved in this task.