title: Third intracellular loop of glucagon like-peptide-1 receptor is coupled with endogenous mono-ADP-ribosyltransferase - novel type of receptor regulation?
abstract: Our previous studies revealed the main role of the third intracellular loop (IC(3)) of glucagon-like peptide-1 receptor (GLP-1 receptor), in G-protein activation, where the presence or absence of agonist and the receptor phosphorylation seemed to be the only regulatory mechanisms. In order to further study the signaling mechanisms of GLP-1 receptor, we investigated the effect of the third intracellular loop-derived peptide on endogenous mono-ADP-ribosyltransferase mediated mono-ADP-ribosylation of G-proteins β subunit in CHO cells. Results showed an inhibitory effect of IC(3) peptide on mono-ADP-ribosylation of β subunit, obviously via the mechanism of competitive inhibition. Excluding the activity of this inhibitory mechanism via pertussis toxin-sensitive G proteins, the direct functional coupling of IC(3) of GLP-1 receptor and endogenous mono-ADP-ribosyltransferase was confirmed. We suggest that this arginine specific enzymatic posttranslational modification of third intracellular loop of GLP-1 receptor might represent a possible novel mechanism of receptor activity regulation and the pharmacological potential in treatment of diabetes mellitus type 2.
authors.affiliation: Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Deželak
authors.forename: Aljoša
authors.initials: A
authors.lastname: Bavec
mesh_terms: D036002:ADP Ribose Transferases / Q000378:metabolism*; D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D044387:GTP-Binding Protein beta Subunits / Q000378:metabolism; D000067757:Glucagon-Like Peptide-1 Receptor; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D037342:Pertussis Toxin / Q000494:pharmacology; D011485:Protein Binding; D018027:Receptors, Glucagon / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D044387:GTP-Binding Protein beta Subunits; D000067757:Glucagon-Like Peptide-1 Receptor; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D000246:Adenosine Diphosphate Ribose; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D036002:ADP Ribose Transferases; D037342:Pertussis Toxin