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Vol. 53, Issue 3, 524-529, March 1998

The Third Extracellular Loop of the beta 2-Adrenergic Receptor Can Modulate Receptor/G Protein Affinity

Ming-Ming Zhao,1 Robert J. Gaivin, and Dianne M. Perez

Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, Ohio 44195

Chimeric receptors of the beta 2-adrenergic receptor in which the extracellular loops were replaced with the corresponding amino acids of the alpha 1a-adrenergic receptor were generated to measure changes in alpha 1-antagonist affinity. Although no changes in alpha 1-antagonist affinity were measured in the beta 2/alpha 1a chimeras, a decreased IC50 (10-fold) for agonists as compared with wild type beta 2 control was found because of the replacement of the third extracellular loop (EX3). These agonist high affinity changes were because of a greater proportion of high affinity sites (2-fold) that were convertible to low affinity sites with guanosine 5'-3-O-(thio)triphosphate. Adenylate cyclase activity evoked by the EX3 chimera showed commensurate increases in the basal signal transduction as well as the isoproterenol-stimulated potency, suggesting constitutive activity. However, unlike other constitutively active adrenergic receptor mutants in which the mutation causes G protein-independent changes, the mechanism of the EX3 chimera seems to be attributable to a greater ease with which the active ternary complex is formed because of a higher affinity/coupling of the G protein. Although the changes because of EX3 are indirect and most likely affect helical packing, they support an emerging hypothesis that G protein-coupled receptors have evolved their structure-function relationships to constrain the receptor in an inactive state.

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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