In vivo activation of insulin receptor tyrosine kinase by melatonin in the rat hypothalamus.
Melatonin is the pineal hormone that acts via a pertussis toxin-sensitive G-protein to inhibit adenylate cyclase. However, the intracellular signalling effects of melatonin are not completely understood. Melatonin receptors are mainly present in the suprachiasmatic nucleus (SCN) and pars tuberalis of both humans and rats. The SCN directly controls, amongst other mechanisms, the circadian rhythm of plasma glucose concentration. In this study, using immunoprecipitation and immunoblotting, we show that melatonin induces rapid tyrosine phosphorylation and activation of the insulin receptor beta-subunit tyrosine kinase (IR) in the rat hypothalamic suprachiasmatic region. Upon IR activation, tyrosine phosphorylation of IRS-1 was detected. In addition, melatonin induced IRS-1/PI3-kinase and IRS-1/SHP-2 associations and downstream AKT serine phosphorylation and MAPK (mitogen-activated protein kinase) phosphorylation, respectively. These results not only indicate a new signal transduction pathway for melatonin, but also a potential cross-talk between melatonin and insulin.
Anhê
Gabriel F
GF
Departamento de Fisiologia e Biofisica, ICB, USP, São Paulo, Brazil.
Caperuto
Luciana C
LC
Pereira-Da-Silva
Marcio
M
Souza
Lilian C
LC
Hirata
A Emiko
AE
Velloso
Lício A
LA
Cipolla-Neto
José
J
Carvalho
Carla R O
CR
D000818:Animals; D004305:Dose-Response Relationship, Drug; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007276:Injections, Intraventricular; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008550:Melatonin / Q000494:pharmacology*; D019950:Mitogen-Activated Protein Kinase 1 / Q000187:drug effects / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011485:Protein Binding / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology; D014363:Tryptamines / Q000494:pharmacology
D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008550:Melatonin; D019950:Mitogen-Activated Protein Kinase 1; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D044094:Receptors, Melatonin; D013764:Tetrahydronaphthalenes; D014363:Tryptamines; C114459:4-phenyl-2-propionamidotetraline; C526292:IRS1 protein, human; C526296:Irs1 protein, rat; C057154:luzindole; C410467:insulin receptor tyrosine kinase; C494920:Akt1 protein, rat; C516727:Ptpn11 protein, rat