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The role of Olfr78 in the breathing circuit of mice

Nature volume 561, pages E33–E40 (2018)Cite this article

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arising from A. J. Chang, F. E. Ortega, J. Riegler, D. V. Madison & M. A. Krasnow Nature 527, 240–244 (2015); https://doi.org/10.1038/nature15721

The carotid body is essential for the adaptation of mammals to environmental or pathological conditions that result in hypoxaemia. In response to hypoxia, neuron-like oxygen-sensitive glomus cells in the carotid body release neurotransmitters that rapidly activate afferent sensory fibres that stimulate the respiratory centre and induce hyperventilation1, although the mechanisms by which glomus cells detect changes in blood oxygen tension remain unclear2,3. Single dissociated glomus cells can respond robustly to hypoxia when superfused with standard, lactate-free hypoxic solutions; it was therefore surprising that Chang et al.4 claimed that lactate activation of the odorant receptor Olfr78, which is abundantly expressed in the carotid body, is required for oxygen regulation of breathing. We are unable to replicate these findings and show that Olfr78−/− mice have a normal ventilatory response to hypoxia and that the physiological responses of single glomus cells to hypoxia and lactate are indistinguishable between wild-type and Olfr78−/− mice. There is a Reply to this Comment by Chang, A. J. et al. Nature 561, https://doi.org/10.1038/s41586-018-0547-7 (2018).

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Fig. 1: Ventilatory responses to hypoxia of wild-type and Olfr78−/− mice.
Fig. 2: Physiological responses to acute hypoxia in carotid body slices and single dissociated glomus cells from wild-type and Olfr78−/− mice.

Data availability

Data are available upon request from the corresponding author.

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Authors and Affiliations

  1. Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain

    Hortensia Torres-Torrelo, Patricia Ortega-Sáenz & José López-Barneo

  2. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Seville, Spain

    Hortensia Torres-Torrelo, Patricia Ortega-Sáenz & José López-Barneo

  3. Department of Physiology, Development & Neuroscience, University of Cambridge, Physiological Laboratory, Cambridge, UK

    David Macías & Randall S. Johnson

  4. Max Planck Research Unit for Neurogenetics, Frankfurt, Germany

    Masayo Omura & Peter Mombaerts

  5. Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC, USA

    Ting Zhou & Hiroaki Matsunami

  6. Department of Neurobiology and Duke Institute for Brain Sciences, Duke University Medical Center, Durham, NC, USA

    Hiroaki Matsunami

  7. Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden

    Randall S. Johnson

Authors
  1. Hortensia Torres-Torrelo
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  2. Patricia Ortega-Sáenz
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  3. David Macías
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  4. Masayo Omura
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  5. Ting Zhou
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  6. Hiroaki Matsunami
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  7. Randall S. Johnson
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  8. Peter Mombaerts
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  9. José López-Barneo
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Contributions

All authors participated in the design of the experiments. H.T.-T., P.O.-S., D.M., M.O. and T.Z. performed the experiments and analysed data. R.S.J., J.L.-B., H.M. and P.M. supervised the study and wrote the manuscript.

Corresponding author

Correspondence to José López-Barneo.

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Declared none.

Extended data figures and tables

Extended Data Fig. 1 Ventilatory responses to hypoxia and genotyping in wild-type and Olfr78−/− mice.

a, Plethysmographic recordings (breathing frequency as a measure of time) of the ventilatory response to hypoxia (10% O2). Each data point represents the mean ± s.e.m. of the values for control mice (n = 10; 7 wild-type and 3 heterozygous mice pooled together) and Olfr78−/− mice (n = 9) of the FRA colony. The grey-shaded area indicates the first five consecutive measurements after the transition to hypoxia used for quantification (see Supplementary Information). b, Breathing frequency in normoxia (basal) and during exposure to hypoxia (10% O2) of control FRA mice (n = 10, 7 wild-type and 3 heterozygous mice) and Olfr78−/− FRA mice (n = 9). Data are mean ± s.e.m. Statistically significant differences compared to basal values are indicated; *P < 0.001. c, Schematic of the wild-type and gene-targeted Olfr78 alleles. Olfr78, intronless coding region of Olfr78; GFP, green-fluorescent protein; IRES, internal ribosome entry site; taulacZ, fusion of bovine tau with β-galactosidase. The arrows indicate the position and orientation of PCR primers used for genotyping. d, Genotyping of genomic tail DNA of wild-type (Olfr78+/+) and homozygous (Olfr78−/−) mice by PCR. The PCR primer pair ‘CONTROL’ amplifies the wild-type Olfr78 allele; the PCR primer pair ‘GFP’ amplifies internal GFP sequences; and the PCR primer pair ‘MUT’ amplifies the gene-targeted Olfr78 allele.

Extended Data Fig. 2 Ventilatory responses to hypoxia and hypercapnia in wild-type and Olfr78−/− mice.

a, b, Representative examples of plethysmographic recordings (breathing frequency) during exposure to hypoxia (10% O2) and hypercapnia (5% CO2) in a wild-type FRA mouse and in a Olfr78−/− FRA mouse. c, Plethysmographic recordings (breathing frequency as a measure of time) of the ventilatory response to hypercapnia (5% CO2) performed on wild-type (n = 10) and Olfr78−/− (n = 10) FRA mice. Each data point represents the mean ± s.e.m. of the values for the group of 10 mice. CO2 (percentage CO2) tensions are indicated at the bottom. d, Breathing frequency during exposure to hypercapnia (5% CO2) in Olfr78−/− FRA mice (n = 10) compared to their wild-type littermates (n = 10). e, Breathing frequency during exposure to hypoxia (10% O2) in Olfr78−/− LEX mice compared to wild-type LEX mice (n = 10 for each genotype, 7 pairs in a C57BL/6 background, 3 pairs in a C57BL/6:129S5 mixed background, 9 out of 10 pairs are sex-matched littermates). f, Breathing frequency during exposure to hypoxia (10% O2) in Olfr78−/− JAX mice (n = 6) compared to their wild-type littermates (n = 5), in experiments carried out at Duke University. g, Plethysmographic recordings (breathing frequency as a measure of time) of the ventilatory response to hypercapnia (5% CO2) performed on wild-type (n = 7) and Olfr78−/− (n = 7) JAX mice. Each data point represents the mean ± s.e.m. CO2 (percentage CO2) tensions are indicated at the bottom. h, Breathing frequency during exposure to hypercapnia (5% CO2) in Olfr78−/− JAX mice (n = 7) compared to their wild-type littermates (n = 7). Data are mean ± s.e.m. Statistically significant differences compared to basal values are indicated; *P < 0.001.

Extended Data Fig. 3 Changes in cellular parameters elicited by lactate in carotid body glomus cells from wild-type and Olfr78−/− FRA mice.

a, Immunohistochemical detection of GFP and tyrosine hydroxylase (TH) in a carotid body slice from an Olfr78−/− FRA mouse. b, Representative examples of quantal dopamine secretion from glomus cells in carotid body slices of wild-type FRA mice (left) and Olfr78−/− FRA mice (right) in response to external application of l-lactate (sodium lactate, 5 mM). c, Representative examples of increase in cytosolic Ca2+ levels elicited by l-lactate (5 mM) in single dissociated glomus cells from wild-type FRA mice (left) and Olfr78−/− FRA mice (right). d, Amplitude of changes in cytosolic Ca2+ levels induced by lactate in glomus cells from wild-type FRA mice (green, n = 16 cells, 5 mice) and Olfr78−/− FRA mice (purple, n = 14 cells, 5 mice) relative to the signal obtained with 40 mM K+. Data are mean ± s.e.m.

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Torres-Torrelo, H., Ortega-Sáenz, P., Macías, D. et al. The role of Olfr78 in the breathing circuit of mice. Nature 561, E33–E40 (2018). https://doi.org/10.1038/s41586-018-0545-9

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