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|Title:||Monotreme glucagon-like peptide-1 in venom and gut: one gene - two very different functions.|
|Authors:||Tsend-Ayush, Enkhjargal;He, Chuan;Myers, Mark A;Andrikopoulos, Sof;Wong, Nicole;Sexton, Patrick M;Wootten, Denise;Forbes, Briony E;Grutzner, Frank|
|Affiliation:||Robinson Research Institute, School of Biological Sciences, The University of Adelaide, South Australia, Australia|
School of Applied and Biomedical Sciences, Federation University Australia, Mount Helen, Victoria, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Monash Institute of Pharmaceutical Sciences and Department of Pharmacology, Monash University, Parkville, Victoria, Australia
School of Medicine, Flinders University, Bedford Park, South Australia, Australia
|Citation:||Scientific reports 2016; 6: 37744|
|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.|
Research Support, Non-U.S. Gov't
|Appears in Collections:||Journal articles|
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