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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

Delineation of the motilin domain involved in desensitization and internalization of the motilin receptor by using full and partial antagonists.

Studies with fragments of the gastrointestinal peptide, motilin, indicate that the C-terminal region of this peptide plays an important role in the desensitization of the motilin receptor (MTLR). AIM: To verify this hypothesis we studied the desensitization, phosphorylation and internalization induced by motilin analogues of different chain length with agonistic and antagonistic properties in CHO-MTLR cells. METHODS: We studied motilin [1-22], the [1-14] fragment, the analogues Phe(3)[1-22] and Phe(3)[1-14], and two putative antagonists, GM-109 and MA-2029 (modified 1-4 and 1-3 fragments). Activation and desensitization (2h preincubation with the motilin analogues 10muM) were studied in CHO-MTLR cells by an aequorin based luminescence assay. Phosphorylation was studied by immunoprecipitation and internalization was visualized in CHO-MTLR cells containing an enhanced green fluorescent protein (CHO-MTLR-EGFP). RESULTS: Motilin [1-22] and [1-14] were more potent than Phe(3)[1-22] and Phe(3)[1-14] (pEC(50): 9.77, 8.78, 7.36 and 6.65, respectively) to induce Ca(2+) release. GM-109 and MA-2029 were without agonist activity. [1-22] and Phe(3)[1-22] decreased the second response to motilin from 78+/-2% to 11+/-3% and 34+/-3% (P<0.001), respectively, whereas [1-14], Phe(3)[1-14], GM-109 and MA-2029 had no desensitizing effect (68+/-5%, 78+/-3%, 78+/-6% and 78+/-5%, respectively, P>0.05). The rank order of MTLR-phosphorylation was: [1-22]>[1-14]>Phe(3)[1-22]=Phe(3)[1-14]>GM-109=MA-2029. Only motilin [1-22] and [1-14] induced receptor MTLR-EGFP internalization as shown by a decrease in membrane fluorescence: 20+/-3% and 7+/-3%, respectively. CONCLUSION: The C-terminus of motilin enhances desensitization, phosphorylation and internalization of the MTLR while modifications of the N-terminus can favor a conformation of the receptor that is less susceptible to phosphorylation and internalization.[1]


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