title: Monotreme glucagon-like peptide-1 in venom and gut: one gene - two very different functions.
abstract: The importance of Glucagon like peptide 1 (GLP-1) for metabolic control and insulin release sparked the evolution of genes mimicking GLP-1 action in venomous species (e.g. Exendin-4 in Heloderma suspectum (gila monster)). We discovered that platypus and echidna express a single GLP-1 peptide in both intestine and venom. Specific changes in GLP-1 of monotreme mammals result in resistance to DPP-4 cleavage which is also observed in the GLP-1 like Exendin-4 expressed in Heloderma venom. Remarkably we discovered that monotremes evolved an alternative mechanism to degrade GLP-1. We also show that monotreme GLP-1 stimulates insulin release in cultured rodent islets, but surprisingly shows low receptor affinity and bias toward Erk signaling. We propose that these changes in monotreme GLP-1 are the result of conflicting function of this peptide in metabolic control and venom. This evolutionary path is fundamentally different from the generally accepted idea that conflicting functions in a single gene favour duplication and diversification, as is the case for Exendin-4 in gila monster. This provides novel insight into the remarkably different metabolic control mechanism and venom function in monotremes and an unique example of how different selective pressures act upon a single gene in the absence of gene duplication.
authors.affiliation: Robinson Research Institute, School of Biological Sciences, The University of Adelaide, South Australia, 5000, Australia.
authors.forename: Enkhjargal
authors.initials: E
authors.lastname: Tsend-Ayush
authors.affiliation: Robinson Research Institute, School of Biological Sciences, The University of Adelaide, South Australia, 5000, Australia.
authors.forename: Chuan
authors.initials: C
authors.lastname: He
authors.affiliation: School of Applied and Biomedical Sciences, Federation University Australia, Mount Helen, Victoria, 3353, Australia.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Myers
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria 3084, Australia.
authors.forename: Sof
authors.initials: S
authors.lastname: Andrikopoulos
authors.affiliation: Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria 3084, Australia.
authors.forename: Nicole
authors.initials: N
authors.lastname: Wong
authors.affiliation: Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, 3052, Australia.
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Sexton
authors.affiliation: Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, 3052, Australia.
authors.forename: Denise
authors.initials: D
authors.lastname: Wootten
authors.affiliation: Robinson Research Institute, School of Biological Sciences, The University of Adelaide, South Australia, 5000, Australia.|School of Medicine, Flinders University, Bedford Park, South Australia, 5042, Australia.
authors.forename: Briony E
authors.initials: BE
authors.lastname: Forbes
authors.affiliation: Robinson Research Institute, School of Biological Sciences, The University of Adelaide, South Australia, 5000, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Grutzner
mesh_terms: D000818:Animals; D005075:Biological Evolution; D002478:Cells, Cultured; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000235:genetics* / Q000378:metabolism; D054795:Incretins / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007413:Intestinal Mucosa / Q000378:metabolism*; D009007:Monotremata; D010455:Peptides / Q000235:genetics; D010802:Phylogeny; D010987:Platypus; D012641:Selection, Genetic; D004442:Tachyglossidae; D014688:Venoms / Q000235:genetics* / Q000378:metabolism*
chemical_list: D054795:Incretins; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide