Impaired carotid body hypoxic sensing in mice deficient in olfactory receptor 78

Abstract

Carotid bodies are the sensory organs for detecting hypoxemia (decreased arterial blood oxygen levels) and ensuing chemo reflex is a major regulator of breathing and blood pressure. Chang et al (2015) proposed that olfactory receptor 78 (Olfr78) plays a major role in hypoxic sensing by the carotid body. However, such a possibility was questioned by a subsequent study ((Torres-Torrelo et al. 2018). The discrepancy between the two reports prompted the present study to reexamine the role of Olfr78 in hypoxic sensing by the carotid body (CB). Studies were performed on age and gender matched Olfr78 knock out mice generated on BL6 and JAX backgrounds and corresponding wild type mice. Breathing was monitored by plethysmography in un-sedated and efferent phrenic nerve activity in anesthetized mice. Carotid body sensory nerve activity was determined ex vivo and [Ca 2+ ]i responses were monitored in isolated glomus cells, the primary O2 sensing cells of the carotid body. Olfr78 null mice on both BL6 and JAX backgrounds exhibited attenuated hypoxic ventilatory response, whereas breathing responses to CO2 were unaffected.The magnitude of hyperoxia-induced depression of breathing (Dejour's test), which is an indirect measure of carotid body hypoxic sensing, was markedly reduced in Olfr78 mutant mice on both background strains. Furthermore, carotid body sensory nerve and glomus cell [Ca 2+ ]i responses to hypoxia were attenuated in BL6 and JAX Olfr78 null mice. These results suggest that Olfr78 plays an important role in hypoxic sensing by the carotid body.Key Words: G-protein coupled receptors, oxygen sensing, sensory nerve activity, hypoxic ventilator response, carotid body chemo reflex. METHODS Preparation of AnimalsExperimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Chicago. Experiments were performed on age-matched adult wild-type (WT) and Olfr78 null mice on C57BL/6 background (BL6, gift from Dr. J. Pluznick, Johns Hopkins University) and on 129P2/OlaHsd background (JAX, gift from Dr. A. Chang, The University of California, San Francisco, UCSF). Measurements of breathingWhole body plethysmography-Ventilation was monitored by whole-body plethysmograph (Buxco, DSI, St. Paul, MN), and O2 consumption and CO2 production were determined by the open-circuit method in un-sedated mice as described (Peng et al. 2006). Ventilation was recorded while the mice breathed 21% or 12% O2-balanced N2. Each gas challenge was given for 5 min.O2 consumption and CO2 production were measured at the end of each 5-min challenge. For determining ventilatory response to CO2, baseline ventilation was determined while mice breathed 100% O2 followed by hypercapnic challenge with 5% CO2-95% O2-balance N2. Sighs, sniffs, and movement-induced changes in breathing were monitored and excluded in the analysis.All recordings were made at an ambient temperature of 25 ± 1 °C. Minute ventilation (VE = Tidal volume, VT x respiratory rate, RR) was calculated and normalized for body weight and expressed as r...

Carotid Body and Metabolic Syndrome: Mechanisms and Potential Therapeutic Targets

“…For many years, different hypotheses of how CB senses hypoxemia and pH have been proposed, but the exact mechanisms are still speculative. The involvement of gasotransmitters [ 53 , 115 ], olfactory receptor Olfr78 activated by lactate [ 119 , 120 ], and mitochondrial-to-membrane signaling [ 121 , 122 ] are some of them. Recently, the model of mitochondrial-to-membrane signaling was extensively reviewed by Ortega-Sáenz and López-Barneo (see [ 18 ]).…”