PILOT STUDY--BAYLOR CHILD HEALTH RESEARCH CENTER

长期使用β 2-肾上腺素能受体激动剂可能与 哮喘控制恶化和非特异性支气管炎增加 响应能力。 这种临床状态的恶化可能与 长期暴露于β 2受体激动剂后受体脱敏。 的 β 2-肾上腺素能受体（β 2AR）与其效应子腺苷酸偶联 环化酶，通过信号转导G/s蛋白。 与激动剂结合， 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，细胞膜受体就会丧失， 内吞进入早期的内体。 如果长时间接触兴奋剂， 有一个损失的总细胞受体（下调），可能是因为 这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， 注定在溶酶体中降解的蛋白质从早期的核内体移动到 分离晚期内体隔室。 拟议的研究将评估 β 2 AR被传递到降解细胞的细胞内途径 细胞器 此外，管理这一进程的机制将是 确定，侧重于小GTTRab 7，细胞 蛋白激酶和β 2AR突变。 这些研究 将导致对β 2AR下调的更好理解， 为开发基于调节 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.