Chen Tingting, Cai Chengyun, Wang Lifeng, Li Shixin, Chen Ling
Department of Pharmacology, School of Pharmacy, Nantong University, Nantong, China.
Jiangsu Province Key Laboratory of Inflammation and Molecular Drug Target, Nantong, China.
Front Pharmacol. 2020 Dec 29;11:589780. doi: 10.3389/fphar.2020.589780. eCollection 2020.
Inhibition of Ras farnesylation in acute has been found to upregulate the α7 nicotinic acetylcholine receptor (α7nAChR) activity. This study was carried out to investigate the effect of chronic administration for 7 days of farnesyl transferase inhibitor lonafarnib (50 mg/kg, intraperitoneally injected) to male mice on the expression and activity of α7nAChR in hippocampal CA1 pyramidal cells. Herein, we show that lonafarnib dose dependently enhances the amplitude of ACh-evoked inward currents ( ), owning to the increased α7nAChR expression and membrane trafficking. Lonafarnib inhibited phosphorylation of c-Jun and JNK, which was related to DNA methylation. In addition, reduced DNA methyltransferase 1 (DNMT1) expression was observed in lonafarnib-treated mice, which was reversed by JNK activator. Lonafarnib-upregulated expression of α7nAChR was mimicked by DNMT inhibitor, and repressed by JNK activator. However, only inhibited DNA methylation did not affect , and the JNK activator partially decreased the lonafarnib-upregulated . On the other hand, lonafarnib also increased the membrane expression of α7nAChR, which was partially inhibited by JNK activator or CaMKII inhibitor, without changes in the α7nAChR phosphorylation. CaMKII inhibitor had no effect on the expression of α7nAChR. Lonafarnib-enhanced spatial memory of mice was also partially blocked by JNK activator or CaMKII inhibitor. These results suggest that Ras inhibition increases α7nAChR expression through depressed DNA methylation of Ras-c-Jun-JNK pathway, increases the membrane expression of α7nAChR resulting in part from the enhanced CaMKII pathway and total expression of this receptor, and consequently enhances the spatial memory.
急性情况下抑制Ras法尼基化已被发现可上调α7烟碱型乙酰胆碱受体（α7nAChR）的活性。本研究旨在探讨对雄性小鼠连续7天腹腔注射法尼基转移酶抑制剂洛那法尼（50mg/kg）对海马CA1锥体细胞中α7nAChR表达和活性的影响。在此，我们表明洛那法尼剂量依赖性地增强了乙酰胆碱诱发的内向电流（ ）的幅度，这归因于α7nAChR表达和膜转运的增加。洛那法尼抑制了与DNA甲基化相关的c-Jun和JNK的磷酸化。此外，在洛那法尼处理的小鼠中观察到DNA甲基转移酶1（DNMT1）表达降低，而JNK激活剂可使其逆转。DNMT抑制剂可模拟洛那法尼上调的α7nAChR表达，而JNK激活剂则可抑制该表达。然而，仅抑制DNA甲基化并不影响 ，且JNK激活剂部分降低了洛那法尼上调的 。另一方面，洛那法尼还增加了α7nAChR的膜表达，这被JNK激活剂或CaMKII抑制剂部分抑制，而α7nAChR的磷酸化没有变化。CaMKII抑制剂对α7nAChR的表达没有影响。JNK激活剂或CaMKII抑制剂也部分阻断了洛那法尼增强的小鼠空间记忆。这些结果表明，Ras抑制通过抑制Ras-c-Jun-JNK途径的DNA甲基化增加α7nAChR表达，部分通过增强CaMKII途径增加α7nAChR的膜表达和该受体的总表达，从而增强空间记忆。
