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, 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.

Does the pathogenesis of SAR-CoV-2 virus decrease at high-altitude?, Respiratory Physiology and amp; Neurobiology (2020), doi: https://doi. J o u r n a l P r e -p r o o fHighlights  COVID-19 infection is decreased in populations living at an altitude of above 3,000 masl  Highland inhabitants may be less susceptible to SARS-CoV-2 virus infection due to physiological acclimatization to hypoxia  High-altitude environmental factors may contribute to reduce the virulence of SARS-CoV-2 ABSTRACTIn the present study we analyze the epidemiologic data of COVID-19 of Tibet and high-altitude regions of Bolivia and Ecuador, and compare to lowland data, to test the hypothesis that high-altitude inhabitants (+2500 m above sea-level) are less susceptible to develop severe adverse effect in acute SARS-CoV-2 virus infection. Analysis of available epidemiological data suggest that physiological adaptations that counterbalance the hypoxic environment altitude may protect from severe impact of acute SARS-CoV-2 virus infection. Potential underlying mechanisms such as: (i) a compromised half-live of the virus caused by the high-altitude environment, and (ii) a hypoxia mediated down regulation of angiotensin-converting enzyme 2 (ACE2), which is the main binding target of SARS-CoV-2 virus in the pulmonary epithelia are discussed.