Mechanisms of severe acute intermittent hypoxia-induced phrenic long-term facilitation.
Mechanisms of severe acute intermittent hypoxia-induced phrenic long-term facilitation.
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严重急性间歇性缺氧诱发膈长期易化的机制。
DOI：
10.1152/jn.00691.2020
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发表时间：
2021
影响因子：
2.5
通讯作者：
Mitchell,GordonS
中科院分区：
文献类型：
--
作者：
Nichols,NicoleL;Mitchell,GordonS
中度急性间歇性缺氧（mAIH; 35-55 mmHg PaO 2）膈神经长时程易化（pLTF），其机制需要激活Gq蛋白偶联5-羟色胺2型受体、MEK/ERK MAP激酶和NADPH氧化酶活性，并受cAMP-PKA信号传导的限制。相反，严重AIH（sAIH; 25-35 mmHg PaO 2）可增加G蛋白偶联腺苷2A型受体依赖性pLTF。另一种G蛋白偶联受体，5-羟色胺7受体，通过需要由环AMP（EPAC）激活的交换蛋白和磷脂酰肌醇3-激酶/Akt（PI 3 K/Akt）激活并受NADPH氧化酶活性限制的机制，参与膈神经运动易化（pMF）。在这里，我们测试了这样的假设，即引起5-羟色胺7（与5-羟色胺2）受体诱导的pMF的相同下游信号传导机制是sAIH诱导的pLTF的基础。在麻醉大鼠中，在鞘内（C4）注射以下抑制剂预处理后比较sAIH诱导的pLTF：1）EPAC（ESI-05）;2）MEK/ERK（UO 126）;3）PKA（KT-5720）;4）PI 3 K/Akt（PI 828）;和5）NADPH氧化酶（apocynin）。与我们的假设部分一致的是，sAIH诱导的pLTF被ESI-05和PI 828消除，并且被夹竹桃麻素略微增强，但是令人惊讶的是，被UO 126消除，并且被KT-5720减弱。sAIH诱导的pLTF的机制反映了Gq和Gspathways到pMF的元素，可能是它们之间复杂的、串扰的相互作用的结果。我们证明，与中度AIH不同，重度AIH诱导的pLTF需要EPAC和PI 3 K/Akt，并受到NADPH氧化酶活性的限制。令人惊讶的是，sAIH诱导的pLTF需要类似于中度AIH诱导的pLTF的MEK/ERK活性，并且通过PKA抑制而降低。我们认为sAIH诱导的pLTF是由中度与重度AIH诱导的pLTF的主导机制之间复杂的相互作用引起的。
Moderate acute intermittent hypoxia (mAIH; 35–55 mmHg PaO2) elicits phrenic long-term facilitation (pLTF) by a mechanism that requires activation of Gqprotein-coupled serotonin type 2 receptors, MEK/ERK MAP kinase, and NADPH oxidase activity and is constrained by cAMP-PKA signaling. In contrast, severe AIH (sAIH; 25–35 mmHg PaO2) elicits Gsprotein-coupled adenosine type 2 A receptor-dependent pLTF. Another Gsprotein-coupled receptor, serotonin 7 receptors, elicits phrenic motor facilitation (pMF) by a mechanism that requires exchange protein activated by cyclic AMP (EPAC) and phosphatidylinositol 3-kinase/Akt (PI3K/Akt) activation and is constrained by NADPH oxidase activity. Here, we tested the hypothesis that the same downstream signaling mechanisms giving rise to serotonin 7 (vs. serotonin 2) receptor-induced pMF underlie sAIH-induced pLTF. In anesthetized rats, sAIH-induced pLTF was compared after pretreatment with intrathecal (C4) injections of inhibitors for:1) EPAC (ESI-05);2) MEK/ERK (UO126);3) PKA (KT-5720);4) PI3K/Akt (PI828); and5) NADPH oxidase (apocynin). In partial agreement with our hypothesis, sAIH-induced pLTF was abolished by ESI-05 and PI828 and marginally enhanced by apocynin but, surprisingly, was abolished by UO126 and attenuated by KT-5720. Mechanisms of sAIH-induced pLTF reflect elements of both Gqand Gspathways to pMF, likely as a consequence of the complex, cross-talk interactions between them.NEW & NOTEWORTHYDistinct mechanisms give rise to pLTF induced by moderate and severe AIH. We demonstrate that, unlike moderate AIH, severe AIH-induced pLTF requires EPAC and PI3K/Akt and is marginally constrained by NADPH oxidase activity. Surprisingly, sAIH-induced pLTF requires MEK/ERK activity similar to moderate AIH-induced pLTF and is reduced by PKA inhibition. We suggest sAIH-induced pLTF arises from complex interactions between dominant mechanisms characteristic of moderate versus severe AIH-induced pLTF.