Abstract
The hCG receptor has recently been cloned and revealed to be a member of the G protein-coupled receptor family (1), Receptor binding of hCG involves surface regions of both protein subunits of the heterodimer hormone (2) and presumably several regions of the large extracellular domain (ECD)(3), which is the unique structure of all sequenced glycorprotein hormone receptors sequenced so far. How this complex binding leads to activation of a signal transduction cascade (G-protem activation and cAMP increase) is still unclear. The carbohydrate chains of hCG (two asparagine linked ones on each subunit) seem to play a critical role in signal transduction since deglycosylated hCG (degly-hCG) binds the receptor with high affinity but without intrinsic activity (2). To elucidate the fnnctional role of the carbohydrate moieties in receptor interaction we chose a MCA based sandwich-iype assay. Previously, we have described fourteen epitopes on the antigenic surface of hCG: 5 epitodes on the a subunit, 5 β subunit epitodes and 4 epitopes resulting form formation of the heterodimer (4). Having assessed that every epitope discovered on soluble hCG is also present on soluble degly-hCG (5) we compared the epitope accessibility of receptor bound hCG and degly-hCG to 125I-labeled MCA. We found that receptor bound hCG exposed only two epitopes (β3 and β5). White all other 12 epitopes were not detectable. In contrast none of the 14 epitopes were accessible on receptor bound degly-hCG. This observation suggests that receptor binding of hCG and degly-hCG results in hormone receptor complexes in which the ECD of the receptor covers most of the respective legands surface, in addition hCG and degly-hCG differ in distinct receptor bound orientations since degly-hCG exposed none of the 14 epitopes and thus seemed to be more buried by the ECD. If these two different mentations of receptor binding would be responsible for differences in signaltransduction competence (agonistic hCG, antagonositic degly-hCG) will be addressed in further investigations. This study shows that MCA against hCG can be used as tools to describe receptor interaction of hCG and hCG-variants, Furthermore, the sandwich assay approach can probably help to investigate receptor binding of hCG-vanants of several patients such as children with the recently described carbohydrate-deficient glycoprotein syndrome (CDG) (6) or hCG secreting tumors.
1. McFarland et al 1989. Science 245:494: 2. Ryan et al 1988. FASEB J 2:2661; 3. Roche et al 1992. Endocrinology 131:268: 4. Schwarz et al 1986. Endocrinology 118:189: S. Schwarz et al 1991. Mol Cell Endocr.nol 80:33: 7. Jaeken et al 99 1. Act Paed Sc Suppl 375.
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Krude, H., Gruterst, A., Berger, P. et al. HORMONE-RECEPTOR INTERACTION OF HUMAN CHORIONIC GONADOTROPIN (hCG) AND US GLYCOSYLATION, VARIANTS. AS STUDIED BY MONOCLONAL ANNTIBODIES (MCA). Pediatr Res 33 (Suppl 5), S72 (1993). https://doi.org/10.1203/00006450-199305001-00416
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DOI: https://doi.org/10.1203/00006450-199305001-00416