5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists
5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists
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DOI：
10.1124/jpet.115.228395
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发表时间：
2016-04-01
影响因子：
3.5
通讯作者：
Schnellmann, Rick G.
中科院分区：
文献类型：
--
作者：
Harmon, Jennifer L.;Wills, Lauren P.;Schnellmann, Rick G.
在急性器官损伤中，线粒体往往功能失调，最近的研究表明，线粒体生物发生（MB）可以加速线粒体和肾脏功能的恢复。我们之前报道了非选择性5-HT2受体激动剂DOI[1-（4-碘-2,5-二甲氧基苯基）丙二胺]诱导肾近端小管细胞（RPTCs）的MB。本研究的目的是确定5-HT2受体在肾脏线粒体基因调控和氧化代谢中的作用。采用5-HT2C受体激动剂CP-809,101[2-[（3-氯苯基）甲氧基]-6-（1-哌嗪基）吡嗪]和拮抗剂SB-242,084[6-氯-2,3-二氢-5-甲基- n -[6-[（2-甲基-3-吡啶基）氧]-3-吡啶基]- 1h -吲哚-1-羧酰胺二盐化物]检测了5-HT2C受体存在和不存在时RPTCs和小鼠肾脏中线粒体基因和氧化代谢的诱导作用。出乎意料的是，CP-809,101和SB-242,084都增加了RPTC呼吸和过氧化物酶体增殖体激活受体γ辅助激活因子-1 α (PGC-1 α) mRNA在RPTC中1-10 nM的表达。此外，CP-809,101和SB-242,084增加了小鼠PGC-1 α和线粒体蛋白NADH脱氢酶亚基1和NADH脱氢酶（泛素）β亚复合物8的mRNA表达。这些化合物增加了5-HT2C受体被小干扰RNA下调的RPTCs和缺乏5-HT2C受体的小鼠肾皮质中的线粒体基因。相比之下，这些化合物增加PGC-1 α mRNA和呼吸的能力在5-HT2A受体小干扰RNA或5-HT2A受体拮抗剂eplivanserin处理的rptc中被阻断。此外，5-HT2A受体激动剂NBOH-2C-CN[4-[2-[[（2-羟基苯基）甲基]氨基]乙基]-2,5-二甲氧基苯腈]在1-100 nM处增加RPTC呼吸作用。这些结果表明，5-HT2A受体的激动作用可诱导MB，而经典的5-HT2C受体激动剂CP-809,101和拮抗剂SB-242,084可通过5-HT2A受体增加线粒体基因和氧化代谢。据我们所知，这是第一个将5-HT2A受体激动作用与线粒体功能联系起来的报告。
In acute organ injuries, mitochondria are often dysfunctional, and recent research has revealed that recovery of mitochondrial and renal functions is accelerated by induction of mitochondrial biogenesis (MB). We previously reported that the nonselective 5-HT2 receptor agonist DOI [1-(4-iodo-2,5-dimethoxyphenyl) propan-2-amine] induced MB in renal proximal tubular cells (RPTCs). The goal of this study was to determine the role of 5-HT2 receptors in the regulation of mitochondrial genes and oxidative metabolism in the kidney. The 5-HT2C receptor agonist CP-809,101 [2-[(3-chlorophenyl)methoxy]-6-(1-piperazinyl)pyrazine] and antagonist SB-242,084 [6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride] were used to examine the induction of renal mitochondrial genes and oxidative metabolism in RPTCs and in mouse kidneys in the presence and absence of the 5-HT2C receptor. Unexpectedly, both CP-809,101 and SB-242,084 increased RPTC respiration and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1 alpha and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) beta subcomplex 8 in mice. These compounds increased mitochondrial genes in RPTCs in which the 5-HT2C receptor was downregulated with small interfering RNA and in the renal cortex of mice lacking the 5-HT2C receptor. By contrast, the ability of these compounds to increase PGC-1 alpha mRNA and respiration was blocked in RPTCs treated with 5-HT2A receptor small interfering RNA or the 5-HT2A receptor antagonist eplivanserin. In addition, the 5-HT2A receptor agonist NBOH-2C-CN [4-[2-[[(2-hydroxyphenyl)methyl]amino]ethyl]-2,5-dimethoxybenzonitrile] increased RPTC respiration at 1-100 nM. These results suggest that agonism of the 5-HT2A receptor induces MB and that the classic 5-HT2C receptor agonist CP-809,101 and antagonist SB-242,084 increase mitochondrial genes and oxidative metabolism through the 5-HT2A receptor. To our knowledge, this is the first report that links 5-HT2A receptor agonism to mitochondrial function.