SPINAL 5-HT7 RECEPTORS AND PROTEIN KINASE A CONSTRAIN INTERMITTENT HYPDXIA-INDUCED PHRENIC LONG-TERM FACILITATION
SPINAL 5-HT7 RECEPTORS AND PROTEIN KINASE A CONSTRAIN INTERMITTENT HYPDXIA-INDUCED PHRENIC LONG-TERM FACILITATION
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DOI：
10.1016/j.neuroscience.2013.06.068
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发表时间：
2013-10-10
期刊：
影响因子：
3.3
通讯作者：
Mitchell, G. S.
中科院分区：
文献类型：
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作者：
Hoffman, M. S.;Mitchell, G. S.
膈神经长期易化(PLTF)是急性间歇性低氧(AIH)诱导的一种5-羟色胺依赖的呼吸可塑性。PLTF需要脊髓GQ蛋白偶联的5-HT2受体(5-HT2)激活，脑源性神经营养因子(BDNF)的新合成及其高亲和力受体TrkB的激活。鞘内注射Gs蛋白偶联受体的选择性激动剂(腺苷2A和5-羟色胺-7；5-HT7)也通过TrkB的“反式激活”诱导长时间的隔膜运动促进。由于在膈运动神经元附近释放的5-羟色胺可能激活多种5-羟色胺受体亚型，我们验证了5-HT7受体激活参与AIH诱导的pLTF的假说。选择性5-羟色胺7受体拮抗剂(SB-269970，5 mU M，12 mU L)鞘内注射于麻醉、迷走神经切断和换气的大鼠于AIH前(3，5分钟发作，11%02)。与预测相反，SB-269970治疗组大鼠的pLTf高于对照组(80+/-11%比AIH后60分钟456%)。舌下LTF不受脊髓5-HT7受体抑制的影响，提示药物作用局限于脊髓。由于5-HT7受体与蛋白激酶A(PKA)偶联，我们验证了PKA抑制AIH诱导的pLTF的假说。与5-HT7受体抑制类似，脊髓PKA抑制(KT-5720,100MU M，15MU L)增强了pLTF(AIH后60min，99+/-15%；p<；0.05)。相反，激活PKA(8-br-cAMP、100 mM、15 mU L)钝化pLTF与对照组相比(AIH后60min分别为16+/-5%和45+/-6%；p<；0.05)。这些发现提示了一种新的机制，即脊髓Gs蛋白偶联的5-HT7受体通过PKA活性抑制AIH诱导的pLTF。(C)2013年IBRO。爱思唯尔有限公司出版。保留所有权利。
Phrenic long-term facilitation (pLTF) is a form of serotonin-dependent respiratory plasticity induced by acute intermittent hypoxia (AIH). pLTF requires spinal Gq proteincoupled serotonin-2 receptor (5-HT2) activation, new synthesis of brain-derived neurotrophic factor (BDNF) and activation of its high-affinity receptor, TrkB. Intrathecal injections of selective agonists for Gs protein-coupled receptors (adenosine 2A and serotonin-7; 5-HT7) also induce long-lasting phrenic motor facilitation via TrkB "trans-activation." Since serotonin released near phrenic motor neurons may activate multiple serotonin receptor subtypes, we tested the hypothesis that 5-HT7 receptor activation contributes to AIH-induced pLTF. A selective 5-HT7 receptor antagonist (SB-269970, 5 mu M, 12 mu l) was administered intrathecally at C4 to anesthetized, vagotomized and ventilated rats prior to AIH (3, 5-min episodes, 11% 02). Contrary to predictions, pLTF was greater in SB-269970 treated versus control rats (80 +/- 11% versus 45 6% 60 min postAIH; p < 0.05). Hypoglossal LTF was unaffected by spinal 5-HT7 receptor inhibition, suggesting that drug effects were localized to the spinal cord. Since 5-HT7 receptors are coupled to protein kinase A (PKA), we tested the hypothesis that PKA inhibits AIH-induced pLTF. Similar to 5-HT7 receptor inhibition, spinal PKA inhibition (KT-5720, 100 mu M, 15 mu l) enhanced pLTF (99 +/- 15% 60 min post-AIH; p < 0.05). Conversely, PKA activation (8-br-cAMP, 100 mu M, 15 mu l) blunted pLTF versus control rats (16 +/- 5% versus 45 +/- 6% 60 min post-AIH; p < 0.05). These findings suggest a novel mechanism whereby spinal Gs protein-coupled 5-HT7 receptors constrain AIH-induced pLTF via PKA activity. (C) 2013 IBRO. Published by Elsevier Ltd. All rights reserved.