The a-catulin/dystrophin-associated protein complex regulates GPCR function

描述（由申请人提供）：？1-肾上腺素能受体（AR）是响应交感激素去甲肾上腺素和肾上腺素的G蛋白偶联受体（GPCR），并且是用于治疗高血压、良性前列腺肥大（BPH）和创伤后应激障碍（PTSD）的治疗靶标。? 1-AR包括3种独特的亚型，？1A，？1B、？1D，其在整个CNS的血管上普遍表达。虽然每个亚型响应去甲肾上腺素/肾上腺素和激活G？Q/11信令，？1D-AR亚型使用不同于？1A和？1B-AR亚型。例如，？1D-ARs刺激血管平滑肌细胞迁移，而？1A和？1B-AR亚型刺激血管平滑肌细胞肥大。分子机制允许？1D-ARs选择性地激活不同于那些使用的途径？1A和？1B-AR亚型仍然是该领域的一个主要谜团。揭示分子机制？1 D-AR用于刺激血管平滑肌细胞迁移将确定新的药物靶点，以治疗CNS血管再狭窄和动脉粥样硬化斑块形成，预防与恶性高血压相关的偏头痛，并降低中风和神经元细胞死亡的可能性。 公共卫生相关性：这项提议将揭示影响体内肾上腺素能通路（或“战斗或逃跑”）的药物如何引起血管形状和功能的变化。这对目前用于治疗高血压、老年男性良性前列腺肥大（BPH）和从伊拉克和阿富汗返回的退伍军人创伤后应激障碍（PTSD）的肾上腺素能药物具有重要意义。这些信息将提供有关在BPH，PTSD和心血管疾病中使用这些药物的长期安全性的关键信息。

DESCRIPTION (provided by applicant): ?1-adrenergic receptors (ARs) are G-protein coupled receptors (GPCRs) that respond to sympathetic hormones norepinephrine and epinephrine, and are therapeutic targets for the treatment of hypertension, benign prostrate hypertrophy (BPH), and post-traumatic stress disorder (PTSD). ?1-ARs comprise 3 unique subtypes, ?1A, ?1B, and ?1D, which are ubiquitously expressed on blood vessels throughout the CNS. Although each subtype responds to norepinephrine/epinephrine and activates G?q/11 signaling, the ?1D-AR subtype performs a specialized role using mechanisms distinct from the ?1A-AR and ?1B-AR subtypes. For example, ?1D-ARs stimulate vascular smooth muscle cell migration, while the ?1A and ?1B-AR subtypes stimulate vascular smooth cell hypertrophy. The molecular mechanisms that permit ?1D-ARs to selectively activate pathways distinct from those used by the ?1A and ?1B-AR subtypes remains a major mystery in the field. Revealing the molecular mechanisms ?1D- ARs use to stimulate vascular smooth cell migration will identify new drug targets to treat CNS blood vessel restenosis and atherosclerotic plaque formation, prevent migraine associated with malignant hypertension and reduce the potential for stroke and neuronal cell death. PUBLIC HEALTH RELEVANCE: This proposal will reveal how drugs affecting the adrenergic pathway (or "fight or flight") in the body cause blood vessels to change in shape and function. This has important implications for adrenergic drugs currently used to treat high blood pressure, benign prostatic hypertrophy (BPH) in elderly males and post-traumatic stress disorder (PTSD) in combat veterans returning from Iraq and Afghanistan. This information will provide crucial information about the long-term safety of using these drugs in BPH, PTSD and cardiovascular disease.