{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T11:10:12Z","timestamp":1743333012856,"version":"3.40.3"},"reference-count":40,"publisher":"The Endocrine Society","issue":"8","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2012,8,1]]},"abstract":"<jats:p>The distribution of transducers of regulated cAMP-response element-binding protein activity (TORC) between the cytoplasm and the nucleus is tightly regulated and represents one of the main mechanisms whereby the cAMP response element activation activities of TORC are controlled. Whereas both cAMP and Ca2+ pathways can cause translocation of TORC, the relative importance of these two pathways in regulating different TORC within the same cell is unclear. In this study, we determined the mechanism that regulated TORC1 translocation and compared it with that of TORC2 in rat pinealocytes. Stimulation of pinealocytes with norepinephrine (NE), although having no effect on Torc1 transcription, caused rapid dephosphorylation of TORC1. Although NE also caused rapid dephosphorylation of TORC2, pharmacological studies revealed that TORC1 dephosphorylation could be induced by both \u03b2-adrenoceptor\/cAMP and \u03b1-adrenoceptor\/intracellular Ca2+ pathways contrasting with TORC2 dephosphorylation being induced mainly through the \u03b2-adrenoceptor\/cAMP pathway. PhosTag gel indicated a different pattern of TORC1 desphosphorylation resulting from the selective activation of \u03b1- or \u03b2-adrenoceptors. Interestingly, only the \u03b1-adrenoceptor\/intracellular Ca2+-mediated dephosphorylation could translocate TORC1 to the nucleus, whereas the \u03b2-adrenoceptor\/cAMP-mediated dephosphorylation of TORC1 was ineffective. In comparison, translocation of TORC2 was induced predominantly by the \u03b2-adrenoceptor\/cAMP pathway. Studies with different protein phosphatase (PP) inhibitors indicated that the NE-mediated translocation of TORC1 was blocked by cyclosporine A, a PP2B inhibitor, but that of TORC2 was blocked by okadaic acid, a PP2A inhibitor. Together these results highlight different intracellular signaling pathways that are involved in the NE-stimulated dephosphorylation and translocation of TORC1 and TORC2 in rat pinealocytes.<\/jats:p>","DOI":"10.1210\/en.2012-1315","type":"journal-article","created":{"date-parts":[[2012,6,9]],"date-time":"2012-06-09T04:16:00Z","timestamp":1339215360000},"page":"3839-3849","source":"Crossref","is-referenced-by-count":4,"title":["Different Signaling Mechanisms Are Involved in the Norepinephrine-Stimulated TORC1 and TORC2 Nuclear Translocation in Rat Pinealocytes"],"prefix":"10.1210","volume":"153","author":[{"given":"J.","family":"McTague","sequence":"first","affiliation":[{"name":"Departments of Physiology (J.M., N.A., R.K., M.F., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N.","family":"Amyotte","sequence":"first","affiliation":[{"name":"Departments of Physiology (J.M., N.A., R.K., M.F., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R.","family":"Kanyo","sequence":"first","affiliation":[{"name":"Departments of Physiology (J.M., N.A., R.K., M.F., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"M.","family":"Ferguson","sequence":"first","affiliation":[{"name":"Departments of Physiology (J.M., N.A., R.K., M.F., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C. L.","family":"Chik","sequence":"first","affiliation":[{"name":"Departments of Physiology (J.M., N.A., R.K., M.F., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A. K.","family":"Ho","sequence":"first","affiliation":[{"name":"Departments of Physiology (J.M., N.A., R.K., M.F., A.K.H.) and Medicine (C.L.C), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada T6G 2H7"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"80","published-online":{"date-parts":[[2012,6,8]]},"reference":[{"key":"2020071612082884800_B1","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1038\/365855a0","article-title":"Phosphorylated CREB binds specifically to the nuclear protein CBP.","volume":"365","author":"Chrivia","year":"1993","journal-title":"Nature"},{"key":"2020071612082884800_B2","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1016\/0092-8674(89)90013-5","article-title":"Cyclic AMP stimulates somatostatin gene transcription by phoshorylation of CREB at serine 133.","volume":"59","author":"Gonzalez","year":"1989","journal-title":"Cell"},{"key":"2020071612082884800_B3","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/35085068","article-title":"Transcriptional regulation by the phosphorylation-dependent factor CREB.","volume":"2","author":"Mayr","year":"2001","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2020071612082884800_B4","doi-asserted-by":"crossref","first-page":"13505","DOI":"10.1074\/jbc.R000025200","article-title":"CREB binding protein and p300 in transcriptional regulation.","volume":"276","author":"Vo","year":"2001","journal-title":"J Biol Chem"},{"key":"2020071612082884800_B5","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/S0896-6273(02)00656-6","article-title":"Phosphorylation of CREB Ser142 regulates light-induced phase shifts of the circadian clock.","volume":"34","author":"Gau","year":"2002","journal-title":"Neuron"},{"key":"2020071612082884800_B6","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1002\/j.1460-2075.1990.tb08099.x","article-title":"Both the basic region and the 'leucine zipper' domain of the cyclic AMP response element binding (CREB) protein are essential for transcriptional activation.","volume":"9","author":"Dwarki","year":"1990","journal-title":"EMBO J"},{"key":"2020071612082884800_B7","doi-asserted-by":"crossref","first-page":"35242","DOI":"10.1074\/jbc.M007293200","article-title":"The structure of a CREB bZIP-somatostatin CRE complex reveals the basis for selective dimerization and divalent cation-enhanced DNA binding.","volume":"275","author":"Schumacher","year":"2000","journal-title":"J Biol Chem"},{"key":"2020071612082884800_B8","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/j.molcel.2003.08.013","article-title":"TORCs: transducers of regulated CREB activity.","volume":"12","author":"Conkright","year":"2003","journal-title":"Mol Cell"},{"key":"2020071612082884800_B9","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1038\/nature03967","article-title":"The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism.","volume":"437","author":"Koo","year":"2005","journal-title":"Nature"},{"key":"2020071612082884800_B10","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1038\/nature06128","article-title":"Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2.","volume":"449","author":"Dentin","year":"2007","journal-title":"Nature"},{"key":"2020071612082884800_B11","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1038\/nrm3072","article-title":"CREB and the CRTC co-activators: sensors for hormonal and metabolic signals.","volume":"12","author":"Altarejos","year":"2011","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2020071612082884800_B12","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1016\/j.cmet.2008.02.010","article-title":"The insulin-regulated CREB coactivator TORC promotes stress resistance.","volume":"7","author":"Wang","year":"2008","journal-title":"Cell Metab"},{"key":"2020071612082884800_B13","doi-asserted-by":"crossref","first-page":"4700","DOI":"10.1073\/pnas.0607524104","article-title":"TORC1 is a calcium- and cAMP-sensitive coincidence detector involved in hippocampal long-term synaptic plasticity.","volume":"104","author":"Kov\u00e1cs","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612082884800_B14","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1210\/en.2009-0963","article-title":"Involvement of transducer of regulated cAMP response element-binding protein activity on corticotrophin releasing hormone transcription.","volume":"151","author":"Liu","year":"2010","journal-title":"Endocrinology"},{"key":"2020071612082884800_B15","doi-asserted-by":"crossref","first-page":"2156","DOI":"10.1016\/j.cub.2004.11.002","article-title":"Activation of cAMP response element-mediated gene expression by regulated nuclear transport of TORC proteins.","volume":"14","author":"Bittinger","year":"2004","journal-title":"Curr Biol"},{"key":"2020071612082884800_B16","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1111\/j.1742-4658.2007.05889.x","article-title":"TORC-SIK cascade regulates CREB activity through the basic leucine zipper domain.","volume":"274","author":"Takemori","year":"2007","journal-title":"FEBS J"},{"key":"2020071612082884800_B17","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1016\/j.cell.2004.09.015","article-title":"The CREB coactivator TORC2 functions as a calcium- and cAMP-sensitive coincidence detector.","volume":"119","author":"Screaton","year":"2004","journal-title":"Cell"},{"key":"2020071612082884800_B18","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1126\/science.168.3934.979","article-title":"Melatonin synthesis: adenosine 3\u20325\u2032-monophosphate and norepinephrine stimulate N-acetyltransferase.","volume":"168","author":"Klein","year":"1970","journal-title":"Science"},{"key":"2020071612082884800_B19","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/0079-6107(89)90002-3","article-title":"Multiple receptor regulation of cyclic nucleotides in rat pinealocytes.","volume":"53","author":"Chik","year":"1989","journal-title":"Prog Biophys Mol Biol"},{"key":"2020071612082884800_B20","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1016\/S0021-9258(19)75847-5","article-title":"\u03b11-Adrenoceptor activation elevates cytosolic calcium in rat pinealocytes by increasing net influx.","volume":"262","author":"Sugden","year":"1987","journal-title":"J Biol Chem"},{"key":"2020071612082884800_B21","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1016\/S0026-895X(25)08563-3","article-title":"Norepinephrine stimulation of pineal cyclic AMP response element-binding protein phosphorylation: primary role of a \u03b2-adrenergic receptor\/cyclic AMP mechanism.","volume":"47","author":"Roseboom","year":"1995","journal-title":"Mol Pharmacol"},{"key":"2020071612082884800_B22","first-page":"38","article-title":"Photoneural regulation of the mammalian pineal gland. Photoperiodism, melatonin and the pineal.","volume":"117","author":"Klein","year":"1985","journal-title":"Ciba Found Symp"},{"key":"2020071612082884800_B23","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/S0248-4900(98)80006-3","article-title":"Control of CREB phosphorylation and its role for induction of melatonin synthesis in rat pinealocytes.","volume":"89","author":"Maronde","year":"1997","journal-title":"Biol Cell"},{"key":"2020071612082884800_B24","doi-asserted-by":"crossref","first-page":"6979","DOI":"10.1074\/jbc.272.11.6979","article-title":"The rat arylalkylamine N-acetyltransferase gene promoter. cAMP activation via a cAMP-responsive element-CCAAT complex.","volume":"272","author":"Baler","year":"1997","journal-title":"J Biol Chem"},{"key":"2020071612082884800_B25","doi-asserted-by":"crossref","first-page":"7606","DOI":"10.1074\/jbc.M808394200","article-title":"Night\/day changes in pineal expression of &gt;600 genes: Central role of adrenergic\/cAMP signaling.","volume":"284","author":"Bailey","year":"2009","journal-title":"J Biol Chem"},{"key":"2020071612082884800_B26","doi-asserted-by":"crossref","first-page":"3033","DOI":"10.1210\/endo.137.7.8770929","article-title":"Melatonin synthesis: analysis of the more than 150-fold nocturnal increase in serotonin N-acetyltransferase messenger ribonucleic acid in the rat pineal gland.","volume":"137","author":"Roseboom","year":"1996","journal-title":"Endocrinology"},{"key":"2020071612082884800_B27","first-page":"307","article-title":"The melatonin rhythm-generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland.","volume":"52","author":"Klein","year":"1997","journal-title":"Recent Prog Horm Res"},{"key":"2020071612082884800_B28","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1210\/en.2011-1112","article-title":"Adrenergic regulation of the distribution of transducer of regulated cAMP-response element-binding protein (TORC2) in rat pinealocytes.","volume":"152","author":"Kanyo","year":"2011","journal-title":"Endocrinology"},{"key":"2020071612082884800_B29","doi-asserted-by":"crossref","first-page":"4221","DOI":"10.1210\/en.2009-0275","article-title":"Salt-inducible kinase 1 in the rat pinealocyte: adrenergic regulation and role in arylalklyamine N-acetyltransferase gene transcription.","volume":"150","author":"Kanyo","year":"2009","journal-title":"Endocrinology"},{"key":"2020071612082884800_B30","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1038\/227680a0","article-title":"Cleavage of structural proteins during the assembly of the head of bacteriophage T4.","volume":"227","author":"Laemmli","year":"1970","journal-title":"Nature"},{"key":"2020071612082884800_B31","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.1210\/endo.141.12.7856","article-title":"Adrenergic regulation of mitogen-activated protein kinase in rat pinealocytes: opposing effects of protein kinase A and protein kinase G.","volume":"141","author":"Ho","year":"2000","journal-title":"Endocrinology"},{"key":"2020071612082884800_B32","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1046\/j.1471-4159.1997.68031078.x","article-title":"\u03b11D L-type Ca2+-channel currents: inhibition by a \u03b2-adrenergic agonist and pituitary adenylate cyclase-activating polypeptide (PACAP) in rat pinealocytes.","volume":"68","author":"Chik","year":"1997","journal-title":"J Neurochem"},{"key":"2020071612082884800_B33","doi-asserted-by":"crossref","first-page":"3523","DOI":"10.1210\/en.2007-0166","article-title":"The role of repressor proteins in the adrenergic induction of type II iodothyronine deiodinase in rat pinealocytes.","volume":"148","author":"Chik","year":"2007","journal-title":"Endocrinology"},{"key":"2020071612082884800_B34","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1073\/pnas.0406871102","article-title":"Melatonin synthesis: 14-3-3-dependent activation and inhibition of arylalkylamine N-acetyltransferase mediated by phosphoserine-205.","volume":"102","author":"Ganguly","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612082884800_B35","doi-asserted-by":"crossref","first-page":"5723","DOI":"10.1210\/en.2004-0880","article-title":"Norepinephrine induction of mitogen-activated protein kinase phosphatase-1 expression in rat pinealocytes: distinct roles of \u03b1- and \u03b2-adrenergic receptors.","volume":"145","author":"Price","year":"2004","journal-title":"Endocrinology"},{"key":"2020071612082884800_B36","doi-asserted-by":"crossref","first-page":"D961","DOI":"10.2741\/A336","article-title":"Physiologic importance of protein phosphatase inhibitors.","volume":"3","author":"Oliver","year":"1998","journal-title":"Front Biosci"},{"key":"2020071612082884800_B37","first-page":"E458","article-title":"Phosphatase inhibitors potentiate adrenergic-stimulated cAMP and cGMP production in rat pinealocytes.","volume":"268","author":"Ho","year":"1995","journal-title":"Am J Physiol"},{"key":"2020071612082884800_B38","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1113\/jphysiol.1997.sp021930","article-title":"Stimulation of a nicotinic ACh receptor causes depolarization and activation of L-type Ca2+ channels in rat pinealocytes.","volume":"499","author":"Letz","year":"1997","journal-title":"J Physiol"},{"key":"2020071612082884800_B39","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1073\/pnas.80.2.599","article-title":"Postsynaptic \u03b1-adrenergic receptors potentiate the \u03b2-adrenergic stimulation of pineal serotonin N-acetyltransferase.","volume":"80","author":"Klein","year":"1983","journal-title":"Proc Natl Acad Sci USA"},{"key":"2020071612082884800_B40","doi-asserted-by":"crossref","first-page":"1436","DOI":"10.1111\/j.1471-4159.1993.tb03306.x","article-title":"Calcium potentiates cyclic AMP stimulation of pineal arylalkylamine N-acetyltransferase.","volume":"60","author":"Yu","year":"1993","journal-title":"J Neurochem"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/8\/3839\/8982656\/endo3839.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/endo\/article-pdf\/153\/8\/3839\/8982656\/endo3839.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,30]],"date-time":"2025-03-30T10:28:40Z","timestamp":1743330520000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/153\/8\/3839\/2424114"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,6,8]]},"references-count":40,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2012,8,1]]}},"URL":"https:\/\/doi.org\/10.1210\/en.2012-1315","relation":{},"ISSN":["0013-7227","1945-7170"],"issn-type":[{"type":"print","value":"0013-7227"},{"type":"electronic","value":"1945-7170"}],"subject":[],"published":{"date-parts":[[2012,6,8]]}}}