Research On The Adaptive Evolution And Function Of GPR39 In Vertebrates

G protein-coupled receptors（GPCRs）are widely involved in the physiological and pathological processes of vertebrates,and have been the most important target for new drug discovery and research.Among about 800 GPCRs,orphan GPCRs are a class of GPCRs with unknown endogenous ligands and are considered as potential targets for drug development.Therefore,it is of great clinical significance to identify its endogenous ligands for deorphanization,which has been widely concerned by scholars.However,more and more studies proved that GPCRs,including many orphan GPCRs,can constitutively activate G protein singling in a ligand-independent manner.G protein-coupled receptor 39（GPR39）is a class of orphan GPCR with constitutive activity.In this paper,we first performed a phylogenetic and selection analysis of GPR39 in vertebrates.We found GPR39 underwent positive selection in different branches of vertebrates,and positive selection sites of different species were located in different domains of receptor.Second,we demonstrated that Human GPR39,Chicken GPR39,Frog GPR39 and Zebrafish GPR39 can constitutively activate Gq and G12 signaling pathways in a ligand independent manner.Compared with other species,Zebrafish GPR39 can also constitutively activates Gs signaling pathway in a ligand-independent manner and Zebrafish-H296^7.35 site is crucial for the activity of Gs signaling pathway.We further found that the positive selection sites of different species have different effects on different G protein signaling pathways.Our results revealed:orphan receptor GPR39 underwent selection pressure in different branches of vertebrates,and adaptive evolution of GPR39 to diverse directions leading to different constitutive activity in vertebrates.