title: 5-HT2 Receptor Regulation of Mitochondrial Genes: Unexpected Pharmacological Effects of Agonists and Antagonists.
abstract: 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 γ coactivator-1α (PGC-1α) mRNA expression in RPTCs at 1-10 nM. In addition, CP-809,101 and SB-242,084 increased mRNA expression of PGC-1α and the mitochondrial proteins NADH dehydrogenase subunit 1 and NADH dehydrogenase (ubiquinone) β 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-1α 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.
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Harmon
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Lauren P
authors.initials: LP
authors.lastname: Wills
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Caitlin E
authors.initials: CE
authors.lastname: McOmish
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Elena Y
authors.initials: EY
authors.lastname: Demireva
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Jay A
authors.initials: JA
authors.lastname: Gingrich
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.).
authors.forename: Craig C
authors.initials: CC
authors.lastname: Beeson
authors.affiliation: Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (J.L.H., L.P.W., C.C.B., R.G.S.); Department of Psychiatry, Sackler Institute for Developmental Psychobiology, Columbia University, New York, New York (C.E.M., E.Y.D., J.A.G.); Division of Molecular Psychiatry, Florey Institute of Neuroscience and Mental Health, Melbourne Brain Centre, University of Melbourne, Parkville, Victoria, Australia (C.E.M.); Division of Developmental Neuroscience, New York State Psychiatric Institute, New York, New York (E.Y.D., J.A.G.); and Ralph H. Johnson Veterans Administration Medical Center, Charleston, South Carolina (R.G.S.) schnell@musc.edu.
authors.forename: Rick G
authors.initials: RG
authors.lastname: Schnellmann
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D042967:Electron Transport Complex I / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D007211:Indoles / Q000494:pharmacology; D007687:Kidney Tubules, Proximal / Q000166:cytology / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000187:drug effects / Q000235:genetics*; D010084:Oxidation-Reduction; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010879:Piperazines / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011817:Rabbits; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects* / Q000235:genetics*; D044405:Receptor, Serotonin, 5-HT2C / Q000187:drug effects / Q000235:genetics; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics
chemical_list: C107820:6-chloro-5-methyl-1-((2-(2-methylpyrid-3-yloxy)pyrid-5-yl)carbamoyl)indoline; D000631:Aminopyridines; C518685:CP-809,101; D007211:Indoles; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010879:Piperazines; C485290:Ppargc1a protein, mouse; D011719:Pyrazines; D044402:Receptor, Serotonin, 5-HT2A; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D014157:Transcription Factors; D042967:Electron Transport Complex I