Chang Andy J, Ortega Fabian E, Riegler Johannes, Madison Daniel V, Krasnow Mark A
Department of Biochemistry, Stanford University School of Medicine and Howard Hughes Medical Institute, Stanford, California 94305-5307, USA.
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature. 2015 Nov 12;527(7577):240-4. doi: 10.1038/nature15721.
Animals have evolved homeostatic responses to changes in oxygen availability that act on different timescales. Although the hypoxia-inducible factor (HIF) transcriptional pathway that controls long-term responses to low oxygen (hypoxia) has been established, the pathway that mediates acute responses to hypoxia in mammals is not well understood. Here we show that the olfactory receptor gene Olfr78 is highly and selectively expressed in oxygen-sensitive glomus cells of the carotid body, a chemosensory organ at the carotid artery bifurcation that monitors blood oxygen and stimulates breathing within seconds when oxygen declines. Olfr78 mutants fail to increase ventilation in hypoxia but respond normally to hypercapnia. Glomus cells are present in normal numbers and appear structurally intact, but hypoxia-induced carotid body activity is diminished. Lactate, a metabolite that rapidly accumulates in hypoxia and induces hyperventilation, activates Olfr78 in heterologous expression experiments, induces calcium transients in glomus cells, and stimulates carotid sinus nerve activity through Olfr78. We propose that, in addition to its role in olfaction, Olfr78 acts as a hypoxia sensor in the breathing circuit by sensing lactate produced when oxygen levels decline.
动物已经进化出对氧气可利用性变化的稳态反应，这些反应作用于不同的时间尺度。尽管控制对低氧（缺氧）长期反应的缺氧诱导因子（HIF）转录途径已经确立，但介导哺乳动物对缺氧急性反应的途径仍未得到充分了解。在这里，我们表明嗅觉受体基因Olfr78在颈动脉体的氧敏感球细胞中高度且选择性地表达，颈动脉体是位于颈动脉分叉处的化学感受器官，可监测血氧并在氧气下降时在数秒内刺激呼吸。Olfr78突变体在缺氧时无法增加通气，但对高碳酸血症反应正常。球细胞数量正常且结构上看似完整，但缺氧诱导的颈动脉体活动减弱。乳酸是一种在缺氧时迅速积累并诱导过度通气的代谢产物，在异源表达实验中激活Olfr78，在球细胞中诱导钙瞬变，并通过Olfr78刺激颈动脉窦神经活动。我们提出，除了在嗅觉中的作用外，Olfr78还通过感知氧气水平下降时产生的乳酸，在呼吸回路中充当缺氧传感器。
