title: Receptor activation is distinct from hormone binding in intact lutropin-choriogonadotropin receptors and Asp397 is important for receptor activation.
abstract: Hormone binding to receptors on the cell surface triggers a sequence of events (receptor activation and signal generation) leading to activation of effectors in the cytoplasm. Receptor activation and signal generation are difficult to study as both are intimately associated with hormone binding. The lutropin-choriogonadotropin (LH/CG) receptor offers a unique model to differentiate and examine receptor activation and signal generation from hormone binding. It belongs to a subfamily of glycoprotein hormone receptors within the G-protein-coupled receptor family. This receptor subfamily has several structural features different from the structures of other G-protein-coupled receptors. These receptors consist of a large extracellular N-terminal half and membrane-associated C-terminal half of similar size. The truncated N-terminal half alone is capable of high affinity hormone binding, whereas the truncated C-terminal half alone is capable of low affinity hormone binding and cAMP induction. However, this distinction between the high affinity hormone binding and low affinity hormone binding associated with cAMP induction has not been established in intact receptors. As a step to identify a structural element which is responsible for receptor activation and signal generation, we have identified an extracellular Asp of the C-terminal half of the LH/CG receptor which is unique and common to the glycoprotein hormone receptors. Evidence is presented for the first time that Asp397 is important for induction of cAMP synthesis but not essential for hormone binding. Since extracellular Asp397 cannot interact with G-protein in the cytoplasm, the inability of the mutant LH/CG receptors with an Asp397 substitution to induce cAMP synthesis is likely to be caused by a defect in the intermediate steps (receptor activation and signal generation) between hormone binding and activation of G-protein. Therefore, our results not only demonstrate that receptor activation and signal generation are distinct from high affinity hormone binding in intact LH/CG receptors, but they also identify an amino acid important for the processes.
authors.affiliation: Department of Molecular Biology, University of Wyoming, Laramie 82071-3944.
authors.forename: I
authors.initials: I
authors.lastname: Ji
authors.forename: T H
authors.initials: TH
authors.lastname: Ji
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001224:Aspartic Acid / Q000378:metabolism*; D002478:Cells, Cultured; D006063:Chorionic Gonadotropin / Q000378:metabolism*; D000242:Cyclic AMP / Q000096:biosynthesis; D006801:Humans; D008969:Molecular Sequence Data; D051381:Rats; D011974:Receptors, LH / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D006063:Chorionic Gonadotropin; D011974:Receptors, LH; D001224:Aspartic Acid; D000242:Cyclic AMP