Evolving concepts of partial agonism. The beta-adrenergic receptor as a paradigm.
The exact mechanism of receptor activation at the molecular level are still not known, nor do we completely understand the precise factors that distinguish agonist- and partial agonist-induced activation. Nevertheless, recent years have brought forth an explosion of new information regarding beta-adrenergic receptor structure and ligand-induced activation. Partial agonists are likely intermediate in their ability to interact with crucial serine residues (Ser204 and Ser207) on the beta-adrenergic receptor; these interactions allow either incomplete stimulation of the entire receptor population, or full stimulation of only a portion of the entire receptor population. From the work presented by Tota and Schimerlik for the muscarinic cholinergic receptor (another G-protein coupled receptor), it is likely that partial agonists induce or stabilize receptor conformations that have a lower affinity for their G protein compared to receptors stimulated by a full agonist. Molecular cloning of beta-adrenergic receptors and analyses of mutated and chimeric receptors expressed in transfected systems have indicated that domains of the receptor that bind agonists may be different from those with which antagonists interact. Thus, the ability of a partial agonist to interact with these two different domains may be a determinant of efficacy. Agonists alter the sulfhydryl redox status of the beta-adrenergic receptors in the presence of Gs. Disulfide rearrangement has been postulated to provide a structural constraint which biases G-protein-linked receptors in the "ground state" and may be important for stabilizing the active state of the receptor and holding the agonist/receptor/Gs ternary complex in the high-affinity state. Partial agonists induce this state less efficaciously or are less capable of holding the receptor in the active conformation to allow disulfide exchange to take place. The extent of receptor stimulation may dictate which G proteins are activated by a particular receptor, and thus which cellular effectors are stimulated. Alternatively, the level of activation of a receptor may translate into varying states of activation of a particular G protein (stabilized in part by disulfide bonds). Techniques such as fluorescence energy transfer in reconstitution systems or nuclear magnetic resonance spectroscopy should prove useful in distinguishing among these possible mechanisms. Ultimately, as a long-term goal, X-ray crystallography of unoccupied receptors and receptors liganded by partial or full agonists may provide definitive insights. Although definitive answers are not yet possible, the rapid progress in understanding aspects of receptor structure allows a reformulation of ideas regarding the molecular basis of efficacy and partial agonism.(ABSTRACT TRUNCATED AT 400 WORDS)
Division of Pediatric Cardiology, Stanford University Medical Center, CA 94305-5119.
J R
JR
Jasper
P A
PA
Insel
D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D004220:Disulfides / Q000737:chemistry; D019204:GTP-Binding Proteins / Q000737:chemistry; D007545:Isoproterenol / Q000494:pharmacology; D008958:Models, Molecular; D010869:Pindolol / Q000494:pharmacology; D011433:Propranolol / Q000494:pharmacology; D011943:Receptors, Adrenergic, beta / Q000737:chemistry / Q000187:drug effects*
D000318:Adrenergic beta-Agonists; D004220:Disulfides; D011943:Receptors, Adrenergic, beta; D011433:Propranolol; D010869:Pindolol; D019204:GTP-Binding Proteins; D007545:Isoproterenol