PILOT STUDY--BAYLOR CHILD HEALTH RESEARCH CENTER

β2-肾上腺素能激动剂的长期使用可能与 哮喘控制恶化和非特异性支气管炎增加 响应性。这种临床状态的恶化可能与 长期暴露于β2受体激动剂后的受体脱敏。这个 β_2-肾上腺素能受体(β_2AR)偶联其效应器--腺苷 Cyclase，通过信号转导的G/S蛋白。通过激动剂结合， 由于受体的作用，受体与G/S蛋白迅速解偶联 磷酸化。在几分钟内，就会有膜受体的损失 将内吞作用转化为早期的内吞体体。随着长期接触激动剂， 总细胞受体的丧失(下调)，可能是 溶酶体降解以及受体合成减少的结果。 对其他受体(例如，EGF-R)的研究表明， 注定要在溶酶体中降解，从早期的内切体到 分离较晚的内吞体室。拟议的研究将评估 将β-2AR输送到降解物的细胞内途径 细胞器。此外，规范这一进程的机制将是 决心，专注于小GTP酶Rab7的作用，细胞 蛋白激酶和β-2AR突变在这一过程中。这些研究 将导致对Beta2AR下调的更好理解， 规范方法论为治疗学发展开辟道路 这些受体的细胞运输。

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.