title: Melatonin inhibits insulin secretion in rat insulinoma β-cells (INS-1) heterologously expressing the human melatonin receptor isoform MT2.
abstract: Melatonin exerts some of its effects via G-protein-coupled membrane receptors. Two membrane receptor isoforms, MT1 and MT2, have been described. The MT1 receptor is known to inhibit second messenger cyclic adenosine monophosphate (cAMP) signaling through receptor-coupling to inhibitory G-proteins (G(i) ). Much less is known about the MT2 receptor, but it has also been implicated in signaling via G(i) -proteins. In rat pancreatic β-cells, it has recently been reported that the MT2 receptor plays an inhibitory role in the cyclic guanosine monophosphate (cGMP) pathway. This study addresses the signaling features of the constitutively expressed human recombinant MT2 receptor (hMT2) and its impact on insulin secretion, using a rat insulinoma β-cell line (INS-1). On the basis of a specific radioimmunoassay, insulin secretion was found to be more strongly reduced in the clones expressing hMT2 than in INS-1 controls, when incubated with 1 or 100 nm melatonin. Similarly, cAMP and cGMP levels, measured by specific enzyme-linked immunosorbent assays (ELISAs), were reduced to a greater extent in hMT2 clones after melatonin treatment. In hMT2-expressing cells, the inhibitory effect of melatonin on insulin secretion was blocked by pretreatment with pertussis toxin, demonstrating the coupling of the hMT2 to G(i) -proteins. These results indicate that functional hMT2 expression leads to the inhibition of cyclic nucleotide signaling and a reduction in insulin release. Because genetic variants of the hMT2 receptor are considered to be risk factors in the development of type 2 diabetes, our results are potentially significant in explaining and preventing the pathogenesis of this disease.
authors.affiliation: Saxon Academy of Sciences Leipzig, Leipzig, Germany. eckhard.muehlbauer@medizin.uni-halle.de
authors.forename: Eckhard
authors.initials: E
authors.lastname: Mühlbauer
authors.forename: Elke
authors.initials: E
authors.lastname: Albrecht
authors.forename: Kathleen
authors.initials: K
authors.lastname: Hofmann
authors.forename: Ivonne
authors.initials: I
authors.lastname: Bazwinsky-Wutschke
authors.forename: Elmar
authors.initials: E
authors.lastname: Peschke
mesh_terms: D000818:Animals; D001483:Base Sequence; D015152:Blotting, Northern; D045744:Cell Line, Tumor; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma / Q000378:metabolism*; D007515:Islets of Langerhans / Q000378:metabolism*; D011863:Radioimmunoassay; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D044123:Receptor, Melatonin, MT2 / Q000235:genetics*
chemical_list: D017931:DNA Primers; D007328:Insulin; D044123:Receptor, Melatonin, MT2