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Numerous secondary effects result from the control of the circadian pacemaker and, in seasonal breeders, of the hypothalamic\/pituitary hormonal axes. In mammals, various binding sites for melatonin have been identified, the membrane receptors MT<jats:sub>1<\/jats:sub> and MT<jats:sub>2<\/jats:sub>, which are of utmost chronobiological importance, ROR and RZR isoforms as nuclear receptors from the retinoic acid receptor superfamily, quinone reductase 2, calmodulin, calreticulin, and mitochondrial binding sites. The G protein\u2010coupled receptors (GPCRs) MT<jats:sub>1<\/jats:sub> and MT<jats:sub>2<\/jats:sub> are capable of parallel or alternate signaling via different G\u03b1 subforms, in particular, G\u03b1<jats:sub>i<\/jats:sub><jats:sub>2\/<\/jats:sub><jats:sub>3<\/jats:sub> and G\u03b1<jats:sub>q<\/jats:sub>, and via G\u03b2\u03b3, as well. Multiple signaling can lead to the activation of different cascades and\/or ion channels. Melatonin frequently decreases cAMP, but also activates phospholipase C and protein kinase C, acts via the MAP kinase and PI3 kinase\/Akt pathways, modulates large conductance Ca<jats:sup>2+<\/jats:sup>\u2010activated K<jats:sup>+<\/jats:sup> and voltage\u2010gated Ca<jats:sup>2+<\/jats:sup> channels. MT<jats:sub>1<\/jats:sub> and MT<jats:sub>2<\/jats:sub> can form homo and heterodimers, and MT<jats:sub>1<\/jats:sub> interacts with other proteins in the plasma membrane, such as an orphan GPCR, GPR50, and the PDZ domain scaffolding protein MUPP1, effects which negatively or positively influence signaling capacity. Cross\u2010talks between different signaling pathways, including influences of the membrane receptors on nuclear binding sites, are discussed. \u00a9 2009 International Union of Biochemistry and Molecular Biology, Inc.<\/jats:p>","DOI":"10.1002\/biof.23","type":"journal-article","created":{"date-parts":[[2009,3,12]],"date-time":"2009-03-12T00:27:53Z","timestamp":1236817673000},"page":"183-192","source":"Crossref","is-referenced-by-count":183,"title":["Melatonin: Signaling mechanisms of a pleiotropic agent"],"prefix":"10.1002","volume":"35","author":[{"given":"R\u00fcdiger","family":"Hardeland","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2009,3,11]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01923947"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.smrv.2004.05.002"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1742-4658.2006.05322.x"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-008-8001-x"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1034\/j.1600-079X.2003.02111.x"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.2174\/1874360900901010001"},{"key":"e_1_2_6_8_2","doi-asserted-by":"publisher","DOI":"10.1210\/endo.143.1.8585"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1002\/cne.10477"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1023\/A:1020107915919"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1186\/1743-7075-2-22"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0024-3205(99)00519-6"},{"key":"e_1_2_6_13_2","first-page":"25","article-title":"Ubiquitous melatonin \u2013 Presence and effects in unicells, plants and animals","volume":"2","author":"Hardeland R.","year":"1996","journal-title":"Trends Comp. 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