TY - JOUR
T1 - 5-HT2 receptor regulation of mitochondrial genes
T2 - Unexpected pharmacological effects of agonists and antagonists
AU - Harmon, Jennifer L.
AU - Wills, Lauren P.
AU - McOmish, Caitlin E.
AU - Demireva, Elena Y.
AU - Gingrich, Jay A.
AU - Beeson, Craig C.
AU - Schnellmann, Rick G.
N1 - Funding Information:
This research was supported in part by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grants F30DK091107 and T32DK083262 (to J.L.H.)]; the National Health and Medical Research Council [C.J. Martin Overseas Biomedical Fellowship (to C.E.M.)]; the Brain and Behavior Research Foundation [Young Investigator Award (to C.E.M.)]; the National Institutes of Health National Institute of Mental Health [Grants R21MH099458 and R01MH080116 (to J.A.G.)]; the National Institutes of Health National Institute of General Medical Sciences [Grants R01GM084147 (to R.G.S) and P20GM103542-02 (to South Carolina COBRE in Oxidants, Redox Balance, and Stress Signaling)]; the National Institutes of Health National Center for Research Resources [Grant UL1RR029882]; the Biomedical Laboratory Research and Development Program of the U.S. Department of Veterans Affairs [Grant 5I01 BX-000851 (to R.G.S.)]; and the South Carolina Clinical and Translational Research Institute at the Medical University of South Carolina. Animal facilities were funded by the National Institutes of Health National Center for Research Resources [Grant C06RR015455]. The authors thank Gyda Beeson for help with RPTC culture and the Seahorse XF instrument, Tamilselvan Jayavelu for help with mRNA expression of the 5-HT2A receptors, Sara Garrett for help with the initial oxygen consumption studies, and Dr. Bryan Roth for guidance in the selection of screening compounds.
PY - 2016/4
Y1 - 2016/4
N2 - 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-1a 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. U.S. Government work not protected by U.S. copyright.
AB - 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-1a 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. U.S. Government work not protected by U.S. copyright.
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U2 - 10.1124/jpet.115.228395
DO - 10.1124/jpet.115.228395
M3 - Article
C2 - 26787771
AN - SCOPUS:84962533050
SN - 0022-3565
VL - 357
SP - 1
EP - 9
JO - Journal of Pharmacology and Experimental Therapeutics
JF - Journal of Pharmacology and Experimental Therapeutics
IS - 1
ER -