Farnesyl Transferase Inhibitor Lonafarnib Enhances α7nAChR Expression Through Inhibiting DNA Methylation of CHRNA7 and Increases α7nAChR Membrane Trafficking

Abstract

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 (IACh), 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 IACh, and the JNK activator partially decreased the lonafarnib-upregulated IACh. 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 CHRNA7 via 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.

Ras Inhibitor Lonafarnib Rescues Structural and Functional Impairments of Synapses of Aβ1-42 Mice via α7nAChR-Dependent BDNF Upregulation

“…In this way, we speculate that, as shown in Figure 6C, H-Ras overexpression might result in the downregulation of p-CaMKII, leading to a reduction of a7nAChR cell surface expression, consequently, leading to the downregulation of BDNF. However, lonafarnib also enhanced the a7nAChR surface expression in the AAV-Rhes mice, which might which might be caused by lonafarnib inhibited H-Ras levels in the Rhes-overexpressed mice, similar with the effect of lonafarnib on the control mice (T. Chen et al, 2020).…”

“…AAV-H-Ras, but not AAV-Rhes, could mimic the reduction of a7nAChR cell surface expression and the decrease of BDNF content in the control mice, which were both enhanced by lonafarnib treatment. However, lonafarnib also enhanced the surface expression of a7nAChR in the AAV-Rhes mice, which might be caused by lonafarnib inhibited H-Ras levels in the Rhesoverexpressed mice, similar with the effect of lonafarnib on the control mice, regardless the overexpression of Ras (T. Chen et al, 2020).…”

“…The activation of a7nAChR also triggers BDNF secretion and recruits TrkB receptors onto cell surface in the SH-SY5Y neuroblastoma cells (Serres and Carney, 2006). Our previous study revealed that Ras inhibition by statins or farnesyltransferase inhibitors (FTI, FTI-277, or lonafarnib) could increase the activity and function of a7nAChR in control mice (T. Chen et al, 2016bChen et al, , 2018Chen et al, , 2020. However, the effects of Ras inhibition on the BDNF expression, the structural and functional properties of synapses and the involvement of a7nAChR are still unclear in case of AD.…”