PILOT STUDY--BAYLOR CHILD HEALTH RESEARCH CENTER

长期使用β2-肾上腺素能激动剂可能与 哮喘控制恶化和非特异性支气管炎增加 反应能力。 临床状态的恶化可能与 长期接触β2激动剂后受体脱敏。 的 β2-肾上腺素能受体 (beta2AR) 与其效应器腺苷酸偶联 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 蛋白快速解偶联 磷酸化。 几分钟内，由于膜受体的损失 胞吞进入早期内体。 长时间暴露于激动剂， 总细胞受体损失（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，那些 注定要在溶酶体中降解的物质从早期内体转移到 分离的晚期内体室。 拟议的研究将评估 β2AR 被递送至降解细胞的细胞内途径 细胞器。 此外，调节这一过程的机制将是 确定，重点关注小 GTP 酶 rab7 的作用，细胞 蛋白激酶和β2AR突变在此过程中。 这些研究 将有助于更好地了解 beta2AR 的下调， 为开发基于调节的治疗方法开辟了道路 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.