title: A novel mechanism for regulating hepatic glycogen synthesis involving serotonin and cyclin-dependent kinase-5.
abstract: Hepatic autonomic nerves regulate postprandial hepatic glucose uptake, but the signaling pathways remain unknown. We tested the hypothesis that serotonin (5-hydroxytryptamine [5-HT]) exerts stimulatory and inhibitory effects on hepatic glucose disposal. Ligands of diverse 5-HT receptors were used to identify signaling pathway(s) regulating glucose metabolism in hepatocytes. 5-HT had stimulatory and inhibitory effects on glycogen synthesis in hepatocytes mediated by 5-HT1/2A and 5-HT2B receptors, respectively. Agonists of 5-HT1/2A receptors lowered blood glucose and increased hepatic glycogen after oral glucose loading and also stimulated glycogen synthesis in freshly isolated hepatocytes with greater efficacy than 5-HT. This effect was blocked by olanzapine, an antagonist of 5-HT1/2A receptors. It was mediated by activation of phosphorylase phosphatase, inactivation of glycogen phosphorylase, and activation of glycogen synthase. Unlike insulin action, it was not associated with stimulation of glycolysis and was counteracted by cyclin-dependent kinase (cdk) inhibitors. A role for cdk5 was supported by adaptive changes in the coactivator protein p35 and by elevated glycogen synthesis during overexpression of p35/cdk5. These results support a novel mechanism for serotonin stimulation of hepatic glycogenesis involving cdk5. The opposing effects of serotonin, mediated by distinct 5-HT receptors, could explain why drugs targeting serotonin function can cause either diabetes or hypoglycemia in humans.
authors: Institute of Cellular Medicine, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors: Susan J
authors: SJ
authors: Tudhope
authors: Chung-Chi
authors: CC
authors: Wang
authors: John L
authors: JL
authors: Petrie
authors: Lloyd
authors: L
authors: Potts
authors: Fiona
authors: F
authors: Malcomson
authors: Julius
authors: J
authors: Kieswich
authors: Muhammad M
authors: MM
authors: Yaqoob
authors: Catherine
authors: C
authors: Arden
authors: Laura J
authors: LJ
authors: Hampson
authors: Loranne
authors: L
authors: Agius
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism / Q000502:physiology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis*; D008297:Male; D053858:Metabolic Networks and Pathways / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology / Q000502:physiology*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000494:pharmacology
chemical_list: D007211:Indoles; D008112:Liver Glycogen; D011725:Pyridines; D011758:Pyrroles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D013764:Tetrahydronaphthalenes; C065046:3-(1,2,5,6-tetrahydropyrid-4-yl)pyrrolo(3,2-b)pyrid-5-one; D012701:Serotonin; C094868:SB 206553; D051360:Cyclin-Dependent Kinase 5; C495907:Cdk5 protein, rat; C031349:7-hydroxy-2-N,N-dipropylaminotetralin