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Molecular Mechanisms of ß₂-Adrenergic Receptor Function and Regulation

CardioPulmonary Research Center, University of Cincinnati College of Medicine, Cincinnati, Ohio

Correspondence and requests for reprints should be addressed to Stephen B. Liggett, M.D., University of Cincinnati College of Medicine, 231 Albert Sabin Way, ML 0564, Cincinnati, OH 45267-0564. E-mail: stephen.liggett{at}uc.edu

It is now clear that the ß₂-adrenergic receptor continuously oscillates between various conformations in the basal state, and that agonists act to stabilize one or more conformations. It is conceivable that synthetic agonists might be engineered to preferentially confine the receptor to certain conformations deemed clinically important while having a less stabilizing effect on unwanted conformations. In addition, studies of genetically engineered mice have revealed previously unrecognized cross-talk between the ß₂-receptor and phospholipase C, such that removal of the primary dilating pathway results in downregulation of constrictive pathways and overactivity of the dilating pathway increases the contractile response. These results indicate a dynamic interaction between ß₂-receptor activity and G_q-coupled receptors that constrict the airway. Potentially, then, during chronic ß-agonist therapy, expression of phospholipase C is increased, the functions of G_q-coupled constrictive receptors are enhanced, and there may be an increased tendency for clinical decompensation due to asthma and chronic obstructive pulmonary disease triggers. Antagonists to these receptors might be able to act synergistically with chronic ß-agonists to block the effect of phospholipase C. Alternatively, perhaps novel phospholipase C antagonists would provide the most efficacious approach to blocking the physiologic sequelae of cross-talk between the ß₂-receptor and phospholipase C.

Key Words: asthma • ß-agonist • chronic obstructive pulmonary disease • G protein–coupled receptor • phospholipase C