Oxygen regulation of breathing through an olfactory receptor activated by lactate.
Oxygen regulation of breathing through an olfactory receptor activated by lactate.
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DOI：
10.1038/nature15721
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发表时间：
2015-11-12
期刊：
影响因子：
64.8
通讯作者：
Krasnow MA
中科院分区：
文献类型：
--
作者：
Chang AJ;Ortega FE;Riegler J;Madison DV;Krasnow MA
动物已经进化出对氧气可用性变化的稳态反应，这些反应作用于不同的时间尺度。尽管已经建立了控制低氧（缺氧）长期反应的缺氧诱导因子（HIF）转录途径，但是在哺乳动物中介导对缺氧的急性反应的途径还不很清楚。在这里，我们表明，嗅觉受体Olfr 78是高度和选择性地表达在氧敏感的血管球细胞的颈动脉体，化学感觉器官在颈动脉分叉处，监测血氧和刺激呼吸在几秒钟内，当氧气下降。Olfr78突变体不能增加缺氧时的通气量，但对高碳酸血症反应正常。血管球细胞数量正常，结构完整，但缺氧诱导的颈动脉体活动减少。乳酸盐是一种在缺氧中快速积累并诱导换气过度的代谢物，在异源表达实验中激活Olfr 78，诱导血管球细胞中的钙瞬变，并通过Olfr 78刺激颈动脉窦神经活动。我们建议，除了其在嗅觉中的作用，Olfr 78作为一个缺氧传感器在呼吸回路中通过检测乳酸产生时，氧气水平下降。
Animals have evolved homeostatic responses to changes in oxygen availability that act on different time scales. 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 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.