The chronic use of beta2-adrenergic agonists may be associated with deterioration in asthma control and an increase in nonspecific bronchial responsiveness. This worsening in clinical status may be related to receptor desensitization after prolonged exposure to beta2-agonists. The beta2-adrenergic receptor (beta2AR) couples to its effector, adenylyl cyclase, via a signal transducing G/s protein. With agonist binding, there is a rapid uncoupling of receptor from G/s protein due to receptor phosphorylation. Within minutes, there is loss of membrane receptors due to endocytosis into early endosomes. With prolonged exposure to agonist, there is a loss of total cellular receptor (down-regulation), probably as a result of lysosomal degradation as well as decreased receptor synthesis. Studies of other receptors (for example, EGF-R) suggest that those destined for degradation in lysosomes travel from early endosomes to a separate late endosome compartment. The proposed studies will evaluate the intracellular route by which beta2AR are delivered to degradative organelles. Additionally, the mechanisms regulating this process will be determined, focusing on the roles of the small GTPase rab7, cellular protein kinases, and beta2AR mutations in this process. These studies will lead to an improved understanding of the down-regulation of beta2AR, opening the way for developing therapeutics based on regulating the cellular trafficking of these receptors.
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