The applicant's long term objective is to become an independent investigator in G-protein coupled receptor biology. A well rounded understanding of receptor biochemistry, molecular biology, and relating the knowledge to receptor physiology and pathology is desired. The goal of this project is to understand the molecular basis of corticotropin releasing factor (CRF) receptor regulation. The CRF system is activated in stress. Downregulation and desensitization of the CRF-CRF receptor interaction is critical in termination of the stress response and prevention of the detrimental consequences of persistent activation of the HPA axis. Alterations within the hypothalamic pituitary adrenal (HPA) axis is associated with a number of endocrine related diseases such as Alzheimer's, depression, and sleep and appetite disorders. Understanding the molecular basis of associated with CRF receptors desensitization, particularly type 1 (CRFR1), will help in understanding the various diseases associated with persistent activation of the HPA axis. The first specific aim will examine the hypothesis that CRF induces desensitization through phosphorylation of the receptor. The second specific aim examines the role of CRFR1 phosphorylation in receptor internalization, resensitization and recycling, and/or recruitment of other signaling molecules. The third specific aim assesses the role of G-protein receptor kinase (GRK) and arrestin in CRF-induced CRFR1 desensitization.
