Hypoxia-induced changes in protein s-nitrosylation in female mouse brainstem.
Hypoxia-induced changes in protein s-nitrosylation in female mouse brainstem.
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DOI：
10.1165/rcmb.2013-0359oc
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发表时间：
2015
影响因子：
6.4
通讯作者：
L. Palmer;Kimberly Deronde;K. Brown-Steinke;Sonya A. Gunter;Vinod Jyothikumar;M. Forbes;S. Lewis
中科院分区：
文献类型：
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作者：
L. Palmer;Kimberly Deronde;K. Brown-Steinke;Sonya A. Gunter;Vinod Jyothikumar;M. Forbes;S. Lewis
暴露于缺氧会导致每分钟通气量增加，而在持续暴露期间会减少（滚降）。脑干 N-甲基-D-天冬氨酸受体 (NMDAR) 和神经元一氧化氮合酶 (nNOS) 有助于最初缺氧引起的分钟通气量增加。滚降由血小板衍生生长因子受体-β (PDGFR-β) 和 S-亚硝基谷胱甘肽 (GSNO) 还原酶 (GSNOR) 调节。 S-亚硝基化抑制 NMDAR 和 nNOS 的活性，但增强 GSNOR 的活性。 S-亚硝基化在缺氧通气反应中的重要性尚不清楚。本研究证实雌性 GSNOR(+/-) 和 GSNO(-/-) 小鼠实际上不存在通气骤降，并评估了 GSNOR 在雌性小鼠脑干中的位置，以及低氧挑战期间 GSNOR 活性、蛋白表达和 GSNOR、NMDAR (1, 2A, 2B)、nNOS 和 PDGFR-β 的 S-亚硝基化状态的时间变化。 GSNOR 阳性神经元遍布整个脑干，包括孤束核。 GSNOR、nNOS、所有 NMDAR 亚基和 PDGFR-β 的蛋白质丰度不会因缺氧而改变。 GSNOR 活性和 S-亚硝基化状态随缺氧暂时增加。此外，nNOS S-亚硝基化随着缺氧 3 分钟和 15 分钟而增加。缺氧 15 分钟时，在 NMDAR 2B 中检测到 NMDAR S-亚硝基化的变化。未检测到缺氧引起的 PDGFR-β S-亚硝基化变化。然而，在低氧暴露期间，野生型小鼠脑干中的PDGFR-β磷酸化增加（与滚降一致），而在GSNOR（+/-）小鼠中则没有升高（与缺乏滚降一致）。这些数据表明：（1）S-亚硝基化事件调节缺氧通气反应； (2) NMDAR 2B、nNOS 和 GSNOR 的 S-亚硝基化增加可能导致通气衰减； (3) GSNOR 调节 PDGFR-β 磷酸化。
Exposure to hypoxia elicits an increase in minute ventilation that diminishes during continued exposure (roll-off). Brainstem N-methyl-D-aspartate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS) contribute to the initial hypoxia-induced increases in minute ventilation. Roll-off is regulated by platelet-derived growth factor receptor-β (PDGFR-β) and S-nitrosoglutathione (GSNO) reductase (GSNOR). S-nitrosylation inhibits activities of NMDAR and nNOS, but enhances GSNOR activity. The importance of S-nitrosylation in the hypoxic ventilatory response is unknown. This study confirms that ventilatory roll-off is virtually absent in female GSNOR(+/-) and GSNO(-/-) mice, and evaluated the location of GSNOR in female mouse brainstem, and temporal changes in GSNOR activity, protein expression, and S-nitrosylation status of GSNOR, NMDAR (1, 2A, 2B), nNOS, and PDGFR-β during hypoxic challenge. GSNOR-positive neurons were present throughout the brainstem, including the nucleus tractus solitarius. Protein abundances for GSNOR, nNOS, all NMDAR subunits and PDGFR-β were not altered by hypoxia. GSNOR activity and S-nitrosylation status temporally increased with hypoxia. In addition, nNOS S-nitrosylation increased with 3 and 15 minutes of hypoxia. Changes in NMDAR S-nitrosylation were detected in NMDAR 2B at 15 minutes of hypoxia. No hypoxia-induced changes in PDGFR-β S-nitrosylation were detected. However, PDGFR-β phosphorylation increased in the brainstems of wild-type mice during hypoxic exposure (consistent with roll-off), whereas it did not rise in GSNOR(+/-) mice (consistent with lack of roll-off). These data suggest that: (1) S-nitrosylation events regulate hypoxic ventilatory response; (2) increases in S-nitrosylation of NMDAR 2B, nNOS, and GSNOR may contribute to ventilatory roll-off; and (3) GSNOR regulates PDGFR-β phosphorylation.