761.16 - Olfactory Receptor78 Participates in Carotid Body-Dependent Sympathetic Activation and Hypertension in Murine Models of Obstructive Sleep Apnea
Tuesday, April 5, 2022
8:25 AM – 8:40 AM
Room: 113 B - Pennsylvania Convention Center
Introduction: G protein-coupled receptors (GPCRs) are the arguably the most important drug target. About 50% of the ~800 GPCRs belong to the families of olfactory and taste receptors. While they were originally cloned from sensory organs, in the past decade expression of these genes was discovered in many other tissues. Technical difficulties with functional expression of these receptors in vitro and unavailability of tools for their analysis impeded progress in this field for many years. This session will highlight recent advances facilitating investigations of these understudied GPCRs and insights into their physiological functions, pharmacology and potential role in human disease.
Ying-Jie Peng (University of Chicago), Xiaoyu Su (University of Chicago), Benjamin Wang (University of Chicago), Timothy Mathews (University of Chicago), Jayasri Nanduri (University of Chicago), Nanduri Prabhakar (University of Chicago)
Olfactory receptor (Olfr) 78 participates in carotid body (CB) activation by acute hypoxia. We examined the role of Olfr78 in CB-dependent sympathetic activation and hypertension in: 1) mice treated with chronic intermittent hypoxia (CIH) patterned after blood O2 profiles during obstructive sleep apnea (OSA) and 2) heme oxygenase-2 (HO-2) null mice, which exhibit OSA. CIH treated wild type (WT) mice showed: enhanced CB sensory nerve response to hypoxia and sensory long-term facilitation (sLTF), hypertension, activation of the sympathetic nervous system as evidenced by spectral analysis of inter-beat interval as well as elevated plasma nor-epinephrine (NE) levels. All these responses were absent in Olfr78 null mice. HO-2 null mice showed spontaneous apneas with an apnea index (AI) of 58±1.2 apneas/hour compared to AI of 8±0.8 apneas/hour in WT mice. CBs of HO-2 null mice showed enhanced CB response to hypoxia and sLTF as well as elevated plasma NE levels and hypertension. The magnitude of hypertension correlated to AI in HO-2 null mice (Plt;0.01). In striking contrast, HO-2/Olfr78 double null mice showed stable breathing with an AI of 12±1.3 apneas/hour. HO-2/Olfr78 double null mice showed absence of augmented CB response to hypoxia, sLTF, elevated plasma NE levels and hypertension. These results demonstrate that Olfr78 participates in CB activation and ensuing sympathetic nerve excitation and hypertension in two mouse models of OSA.
