PUBLICATION
Study of GPR81, the Lactate Receptor, from Distant Species Identifies Residues and Motifs Critical for GPR81 Functions
- Authors
- Kuei, C., Yu, J., Zhu, J., Wu, J., Zhang, L., Shih, A., Mirzadegan, T., Lovenberg, T., and Liu, C.
- ID
- ZDB-PUB-110901-10
- Date
- 2011
- Source
- Molecular pharmacology 80(5): 848-58 (Journal)
- Registered Authors
- Keywords
- Gi family, structure-activity relationships and modeling, func. analysis receptor/ion channel mutants, cholesterol metabolism/lipoproteins
- MeSH Terms
-
- Amino Acid Sequence
- Animals
- Cloning, Molecular
- Humans
- Molecular Sequence Data
- Mutagenesis, Site-Directed
- Receptors, G-Protein-Coupled/chemistry
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/physiology*
- Sequence Homology, Amino Acid
- Zebrafish
- PubMed
- 21862690 Full text @ Mol. Pharmacol.
Citation
Kuei, C., Yu, J., Zhu, J., Wu, J., Zhang, L., Shih, A., Mirzadegan, T., Lovenberg, T., and Liu, C. (2011) Study of GPR81, the Lactate Receptor, from Distant Species Identifies Residues and Motifs Critical for GPR81 Functions. Molecular pharmacology. 80(5):848-58.
Abstract
Receptors from distant species may have conserved functions despite significant differences in protein sequences. While the non-critical residues are often changed in distant species, the amino acids critical in receptor functions are often conserved. Studying the conserved residues between receptors from distant species offers valuable information to probe the roles of residues in receptor function. We identified 2 zebrafish receptors (zGPR81-1 and zGPR81-2) that show about 60% identity to human GPR81, GPR109a, and GPR109b but respond only to L-lactate and not to the GPR109a ligands. Protein sequence comparison among zebrafish GPR81s, mammalian GPR81s, GPR109, and GPR109b identified a common structure (6 Cys residues at the extracellular domains that potentially form three disulfide bonds) in this subfamily of receptors. In addition, a number of residues conserved in all GPR81s but not in GPR109s have been identified. Furthermore, we identified a conserved motif, Cys165-Glu166-Ser167-Phe168, at the 2nd extracellular loop of GPR81. Using site-directed mutagenesis, we showed that Arg71 at the TM2 is very critical for GPR81 function. In addition, we demonstrated that the Cys165-Glu166-Ser167-Phe168 motif at the 2nd ECL is critical for GPR81 function, and the conserved 6 Cys residues at the extracellular regions are necessary for GPR81 function. It is important to mention for those residues important for GPR81 function, the corresponding residues, or motifs in GPR109a are also critical for GPR109a function. These findings help us better understand the interaction between lactate and GPR81 and provide useful information for GPR81 ligand design.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping