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Intrinsic Molecular Proton Sensitivity Underlies GPR4 Effects on Retrotrapezoid Nucleus Neuronal Activation and CO2-Stimulated Breathing
Journal of Neuroscience ( IF 4.4 ) Pub Date : 2024-09-04 , DOI: 10.1523/jneurosci.0799-24.2024
Elizabeth C Gonye 1 , Yingtang Shi 1 , Keyong Li 1 , Rachel T Clements 1 , Wenhao Xu 2 , Douglas A Bayliss 3
Affiliation  

An interoceptive homeostatic reflex monitors levels of CO2/H+ to maintain blood gas homeostasis and rapidly regulate tissue acid–base balance by driving lung ventilation and CO2 excretion—this CO2-evoked increase in respiration is the hypercapnic ventilatory reflex (HCVR). Retrotrapezoid nucleus (RTN) neurons provide crucial excitatory drive to downstream respiratory rhythm/pattern-generating circuits, and their activity is directly modulated by changes in CO2/H+. RTN neurons express GPR4 and TASK-2, global deletion of which abrogates CO2/H+ activation of RTN neurons and the HCVR. It has not been determined if the intrinsic pH sensitivity of these proton detectors is required for these effects. We used CRISPR/Cas9 genome editing to generate mice with mutations in either of two pH-sensing histidine residues in GPR4 to determine effects on RTN neuronal CO2/H+ sensitivity and the HCVR. In global GPR4(H81F) and GPR4(H167F) mice, CO2-stimulated breathing and CO2-induced RTN neuronal activation were strongly blunted, with no effect on hypoxia-stimulated breathing. In brainstem slices from GPR4(H81F) mice, peak firing of RTN neurons during bath acidification was significantly reduced compared with GPR4 wild-type mice, and a subpopulation of RTN neurons was rendered pH-insensitive, phenocopying previous results from GPR4-deleted mice. These effects were independent of changes in RTN number/distribution, neuronal excitability or transcript levels for GPR4 and TASK-2. CO2-stimulated breathing was reduced to a similar extent in GPR4(H81F) and TASK-2-deleted mice, with combined mutation yielding no additional deficit in the HCVR. Together, these data demonstrate that the intrinsic pH sensitivity of GPR4 is necessary for full elaboration of the HCVR.



中文翻译:


内在分子质子敏感性是 GPR4 对梯形核神经元激活和 CO2 刺激呼吸影响的基础



内感受稳态反射监测 CO 2 /H +水平,以维持血气稳态并通过驱动肺通气和 CO 2排泄快速调节组织酸碱平衡 - 这种 CO 2引起的呼吸增加是高碳酸血症通气反射 (HCVR) 。梯形后核 (RTN) 神经元为下游呼吸节律/模式生成回路提供重要的兴奋性驱动,它们的活动直接受 CO 2 /H +的变化调节。 RTN 神经元表达 GPR4 和 TASK-2,其整体缺失会消除 RTN 神经元和 HCVR 的 CO 2 /H +激活。尚未确定这些效应是否需要这些质子检测器的固有 pH 灵敏度。我们使用 CRISPR/Cas9 基因组编辑来生成 GPR4 中两个 pH 感应组氨酸残基中任一者发生突变的小鼠,以确定对 RTN 神经元 CO 2 /H +敏感性和 HCVR 的影响。在整体GPR4(H81F)和GPR4(H167F)小鼠中,CO 2刺激的呼吸和CO 2诱导的RTN神经元激活被强烈减弱,对缺氧刺激的呼吸没有影响。在 GPR4(H81F) 小鼠的脑干切片中,与 GPR4 野生型小鼠相比,在浴液酸化过程中 RTN 神经元的峰值放电显着降低,并且 RTN 神经元亚群变得对 pH 不敏感,这与 GPR4 缺失小鼠的先前结果相似。这些效应与 RTN 数量/分布、神经元兴奋性或 GPR4 和 TASK-2 转录水平的变化无关。 GPR4(H81F)和TASK-2缺失小鼠中CO 2刺激的呼吸减少到类似程度,组合突变不会在HCVR中产生额外的缺陷。总之,这些数据表明 GPR4 的内在 pH 敏感性对于 HCVR 的全面阐述是必要的。

更新日期:2024-09-05
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