Nakayama Hitoshi, Numakawa Tadahiro, Ikeuchi Toshihiko
Department of Pharmacology, Nara Medical University, Kashihara, Nara, Japan Division of Protein Biosynthesis, Institute for Protein Research, Osaka University, Suita, Osaka, Japan.
J Neurochem. 2002 Dec;83(6):1372-9. doi: 10.1046/j.1471-4159.2002.01248.x.
Nicotine treatment triggers calcium influx into neuronal cells, which promotes cell survival in a number of neuronal cells. Phosphoinositide (PI) 3-kinase and downstream PI3-kinase target Akt have been reported to be important in the calcium-mediated promotion of survival in a wide variety of cells. We investigated the mechanisms of nicotine-induced phosphorylation of Akt in PC12h cells, in comparison with nicotine-induced ERK phosphorylation. Nicotine induced Akt phosphorylation in a dose-dependent manner. A nicotinic acetylcholine receptor (nAChR) alpha7 subunit-selective inhibitor had no significant effect on nicotine-induced Akt phosphorylation, while a non-selective nAChR antagonist inhibited the phosphorylation. L-type voltage-sensitive calcium channel (VSCC) antagonists, calmodulin antagonist, and Ca2+/calmudulin-dependent protein kinase (CaM kinase) inhibitor prevented the nicotine-induced Akt phosphorylation. Three epidermal growth factor receptor (EGFR) inhibitors prevented the nicotine-induced phosphorylation of both extracellular signal-regulated protein kinase (p42/44 MAP kinase, ERK) and Akt. In contrast, an inhibitor of the Src family tyrosine kinase prevented the nicotine-induced Akt phosphorylation but not ERK phosphorylation. These results suggested that nicotine induces the activation of both PI3-kinase/Akt and ERK pathways via common pathways including non-alpha7-nAChRs, L-type VSCC, CaM kinase II and EGFR in PC12h cells, but Src family tyrosine kinases only participate in the pathway to activate Akt.
尼古丁处理会引发钙离子流入神经元细胞，这在许多神经元细胞中可促进细胞存活。据报道，磷酸肌醇（PI）3激酶及其下游PI3激酶靶点Akt在多种细胞中由钙介导的存活促进过程中发挥重要作用。我们研究了与尼古丁诱导的细胞外信号调节激酶（ERK）磷酸化相比，尼古丁诱导PC12h细胞中Akt磷酸化的机制。尼古丁以剂量依赖的方式诱导Akt磷酸化。烟碱型乙酰胆碱受体（nAChR）α7亚基选择性抑制剂对尼古丁诱导的Akt磷酸化无显著影响，而非选择性nAChR拮抗剂则抑制该磷酸化。L型电压敏感性钙通道（VSCC）拮抗剂、钙调蛋白拮抗剂和Ca2+/钙调蛋白依赖性蛋白激酶（CaM激酶）抑制剂可阻止尼古丁诱导的Akt磷酸化。三种表皮生长因子受体（EGFR）抑制剂可阻止尼古丁诱导的细胞外信号调节蛋白激酶（p42/44丝裂原活化蛋白激酶，ERK）和Akt的磷酸化。相反，Src家族酪氨酸激酶抑制剂可阻止尼古丁诱导的Akt磷酸化，但不能阻止ERK磷酸化。这些结果表明，尼古丁通过包括非α7 - nAChRs、L型VSCC、CaM激酶II和EGFR在内的共同途径在PC12h细胞中诱导PI3激酶/Akt和ERK途径的激活，但Src家族酪氨酸激酶仅参与激活Akt的途径。
