Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, United States.
The University of Toledo, Department of Neuroscience, Toledo, OH, United States.
Biochem Pharmacol. 2021 Jan;183:114349. doi: 10.1016/j.bcp.2020.114349. Epub 2020 Nov 25.
Serotonin neurotransmission is largely governed by the regulation of the serotonin transporter (SERT). SERT is modulated in part by cholesterol, but the role of cholesterol and lipid signaling intermediates in regulating SERT are unknown. Serotonergic neurons were treated with statins to decrease cholesterol and lipid signaling intermediates. Contrary to reported decreases in 5-HT uptake after cholesterol depletion, biochemical and imaging methods both showed that statins increased 5-HT uptake in a fluoxetine-dependent manner. Simvastatin lowered the Km without changing Vmax for 5-HT or SERT distribution to the plasma membrane. Cholesterol repletion did not block enhanced 5-HT uptake by simvastatin but the enhanced uptake was blocked by lipid isoprenylation intermediates farnesyl pyrophosphate and geranylgeranyl pyrophosphate. Blockade of geranylgeranylation alone without statins also enhanced 5-HT uptake. Overall, this study revealed a specific neuronal effect of statin drugs and identified lipid signaling through geranylgeranylation within the isoprenylation pathway regulates SERT in a cholesterol-independent manner.
5-羟色胺能神经传递在很大程度上受 5-羟色胺转运体（SERT）的调节。胆固醇在一定程度上调节 SERT，但胆固醇和脂质信号中间体在调节 SERT 中的作用尚不清楚。用他汀类药物处理 5-羟色胺能神经元以降低胆固醇和脂质信号中间体。与胆固醇耗竭后 5-HT 摄取减少的报道相反，生化和成像方法均表明，他汀类药物以氟西汀依赖的方式增加 5-HT 的摄取。辛伐他汀降低了 5-HT 或 SERT 分布到质膜的 Km，而没有改变 Vmax。胆固醇再补充并没有阻断辛伐他汀增强的 5-HT 摄取，但增强的摄取被法呢基焦磷酸和香叶基焦磷酸这两种脂质异戊烯化中间产物所阻断。没有他汀类药物的单一代谢阻断也增强了 5-HT 的摄取。总的来说，这项研究揭示了他汀类药物的一种特定的神经元作用，并确定了异戊烯化途径内的香叶基化和法尼基化脂质信号通过胆固醇非依赖性方式调节 SERT。
