Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Drive, Madison, WI 53706-1102, USA.
J Appl Physiol (1985). 2012 Oct 15;113(8):1184-93. doi: 10.1152/japplphysiol.00098.2012. Epub 2012 Sep 6.
Acute intermittent hypoxia (AIH) elicits a form of spinal respiratory plasticity known as phrenic long-term facilitation (pLTF). pLTF requires spinal serotonin receptor-2 activation, the synthesis of new brain-derived neurotrophic factor (BDNF), and the activation of its high-affinity receptor tyrosine kinase, TrkB. Spinal adenosine 2A receptor activation elicits a distinct pathway to phrenic motor facilitation (pMF); this BDNF synthesis-independent pathway instead requires new synthesis of an immature TrkB isoform. Since hypoxia increases extracellular adenosine levels, we tested the hypothesis that new synthesis of TrkB and BDNF contribute to AIH-induced pLTF. Furthermore, given that signaling mechanisms "downstream" from TrkB are unknown in either mechanism, we tested the hypothesis that pLTF requires MEK/ERK and/or phosphatidylinositol 3-kinase (PI3K)/Akt activation. In anesthetized Sprague-Dawley rats, an intrathecal catheter at cervical level 4 was used to deliver drugs near the phrenic motor nucleus. Since pLTF was blocked by spinal injections of small interfering RNAs targeting BDNF mRNA but not TrkB mRNA, only new BDNF synthesis is required for AIH-induced pLTF. Pretreatment with a MEK inhibitor (U0126) blocked pLTF, whereas a PI3K inhibitor (PI-828) had no effect. Thus, AIH-induced pLTF requires MEK/ERK (not PI3K/AKT) signaling pathways. When U0126 was injected post-AIH, pLTF development was halted but not reversed, suggesting that ERK is critical for the development but not maintenance of pLTF. Thus, there are clear mechanistic distinctions between AIH-induced pLTF (i.e., BDNF synthesis and MEK/ERK dependent) versus adenosine 2A receptor-induced pMF (i.e., TrkB synthesis and PI3K/Akt dependent).
急性间歇性低氧（AIH）会引起一种称为膈神经长期易化（pLTF）的脊髓呼吸可塑性。pLTF 需要脊髓 5-羟色胺受体-2 的激活、脑源性神经营养因子（BDNF）的合成以及其高亲和力受体酪氨酸激酶 TrkB 的激活。脊髓腺苷 A2A 受体的激活会引起膈神经运动易化（pMF）的另一种途径；这种 BDNF 合成非依赖性途径需要新合成一种不成熟的 TrkB 同工型。由于缺氧会增加细胞外腺苷水平，我们检验了以下假说：即新的 TrkB 和 BDNF 合成有助于 AIH 诱导的 pLTF。此外，鉴于两种机制中都不知道 TrkB 下游的信号机制，我们检验了以下假说：即 pLTF 需要 MEK/ERK 和/或磷脂酰肌醇 3-激酶（PI3K）/Akt 激活。在麻醉的 Sprague-Dawley 大鼠中，使用颈 4 水平的鞘内导管将药物递送至膈神经运动核附近。由于 pLTF 被靶向 BDNF mRNA 的小干扰 RNA 脊髓内注射所阻断，但不被靶向 TrkB mRNA 的小干扰 RNA 所阻断，因此，仅新的 BDNF 合成是 AIH 诱导的 pLTF 所必需的。MEK 抑制剂（U0126）预处理阻断了 pLTF，而 PI3K 抑制剂（PI-828）则没有作用。因此，AIH 诱导的 pLTF 需要 MEK/ERK（而非 PI3K/Akt）信号通路。当在 AIH 后注射 U0126 时，pLTF 的发展被阻止但没有逆转，这表明 ERK 对于 pLTF 的发展至关重要，但对于其维持则并非如此。因此，AIH 诱导的 pLTF（即 BDNF 合成和 MEK/ERK 依赖性）与腺苷 A2A 受体诱导的 pMF（即 TrkB 合成和 PI3K/Akt 依赖性）之间存在明显的机制差异。
