title: Activation of Akt through 5-HT2A receptor ameliorates serotonin-induced degradation of insulin receptor substrate-1 in adipocytes.
abstract: Serotonin (5-hydroxytryptamine, 5-HT) was found to be elevated in the serum of diabetic patients. In this study, we investigate the mechanism of insulin desensitization caused by 5-HT. In 3T3-L1 adipocytes, 5-HT treatment induced the translocation of insulin receptor substrate-1 (IRS-1) from low density microsome (LDM), the important intracellular compartment for its functions, to cytosol, inducing IRS-1 ubiquitination and degradation. Moreover, inhibition of 5-HT-stimulated Akt activation by either ketanserin (a specific 5-HT2A receptor antagonist) or knocking-down the expression of 5-HT2A receptor promoted 5-HT-stimulated IRS-1 dissociation from 14-3-3β in LDM, leading to drastic ubiquitination. Interestingly, sarpogrelate, another antagonist of 5-HT2A receptor, protected IRS-1 from degradation through activation of Akt. This implicates the importance of Akt activation in extending IRS-1 life span through maintaining their optimal sub-location into adipocytes. Taken together, this study suggest that activation of Akt may be able to compensate the adverse effects of 5-HT by stabilizing IRS-1 in LDM.
authors.affiliation: Clinical Research Center for Diabetes, Tokushima University Hospital, Kuramoto-cho, Tokushima 770-8503, Japan. lqk@clin.med.tokushima-u.ac.jp
authors.forename: Qinkai
authors.initials: Q
authors.lastname: Li
authors.forename: Toshio
authors.initials: T
authors.lastname: Hosaka
authors.forename: Nagakatsu
authors.initials: N
authors.lastname: Harada
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Nakaya
authors.forename: Makoto
authors.initials: M
authors.lastname: Funaki
mesh_terms: D048948:14-3-3 Proteins / Q000378:metabolism; D041721:3T3-L1 Cells; D052438:Adipocytes, White / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D055550:Protein Stability / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000819:agonists* / Q000378:metabolism; D034622:RNA Interference; D044402:Receptor, Serotonin, 5-HT2A / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D048948:14-3-3 Proteins; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D044402:Receptor, Serotonin, 5-HT2A; D058826:Serotonin 5-HT2 Receptor Agonists; D058830:Serotonin 5-HT2 Receptor Antagonists; D012701:Serotonin; C514862:Akt1 protein, mouse; D051057:Proto-Oncogene Proteins c-akt