Department of Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagosima-shi, Kagoshima 890-8544, Japan.
J Mol Neurosci. 2012 Nov;48(3):550-7. doi: 10.1007/s12031-012-9754-0. Epub 2012 Mar 30.
Pituitary adenylate cyclase-activating polypeptide (PACAP) increases neurite outgrowth, although signaling via its receptor PACAP-specific receptor (PAC1R) has not been fully characterized. Because mitochondria also play an important role in neurite outgrowth, we examined whether mitochondria contribute to PACAP-mediated neurite outgrowth. When mouse primary hippocampal neurons and Neuro2a cells were exposed to PACAP, neurite outgrowth and the mitochondrial membrane potential increased in both cell types. These results were reproduced using the PAC1R-specific agonist maxadilan and the adenylate cyclase activator forskolin, whereas the protein kinase A inhibitor H89 and mitochondrial uncoupling agent carbonyl cyanide m-chlorophenyl hydrazone (CCCP) inhibited these effects. Expression levels of peroxisome proliferator-activated receptor γ coactivator 1α (Pgc1α), a master regulator of mitochondrial activation, and its downstream effectors, such as cytochrome C and cytochrome C oxidase subunit 4, increased in response to PACAP. Knocking down Pgc1α expression using small interfering RNA or treatment with CCCP significantly attenuated neurite outgrowth and reduced the mitochondrial membrane potential in PACAP-treated cells. These data suggest that mitochondrial activation plays a key role in PACAP-induced neurite outgrowth via a signaling pathway that includes PAC1R, PKA, and Pgc1α.
垂体腺苷酸环化酶激活肽（PACAP）可促进神经突生长，但其受体 PACAP 特异性受体（PAC1R）的信号转导尚未完全阐明。由于线粒体在神经突生长中也起着重要作用，我们研究了线粒体是否参与 PACAP 介导的神经突生长。当将 PACAP 暴露于原代培养的海马神经元和 Neuro2a 细胞时，两种细胞类型的神经突生长和线粒体膜电位均增加。这些结果可以通过使用 PAC1R 特异性激动剂 maxadilan 和腺苷酸环化酶激活剂 forskolin 来重现，而蛋白激酶 A 抑制剂 H89 和线粒体解偶联剂羰基氰化物 m-氯苯基腙（CCCP）则抑制了这些作用。过氧化物酶体增殖物激活受体 γ 共激活因子 1α（Pgc1α）的表达水平增加，Pgc1α 是线粒体激活的主要调节因子，其下游效应物，如细胞色素 C 和细胞色素 C 氧化酶亚基 4，也随之增加。用小干扰 RNA 敲低 Pgc1α 的表达或用 CCCP 处理可显著减弱 PACAP 处理细胞的神经突生长并降低线粒体膜电位。这些数据表明，通过包括 PAC1R、PKA 和 Pgc1α 在内的信号通路，线粒体的激活在 PACAP 诱导的神经突生长中起着关键作用。
