BECAS MAX PLANCK / FUNDACIÓN BUNGE Y BORN / FUNDACIÓN WILLIAMS
Molecular mechanisms involved in CRHR1 signaling in the central nervous system
María Carolina Inda
Max Planck Institute of Psychiatry
Corticotropin-releasing hormone (CRH) and its type 1 receptor coordinate the neuroendocrine and behavioral adaptation to stress, and are causally linked to the development of affective disorders. Besides its role as the driver of the hypothalamic-pituitary-adrenal axis, CRH functions as a neuromodulator in extra-hypothalamic circuits affecting glutamatergic and dopaminergic transmission as well as neuronal architecture. In most systems, the activation of the G-protein-coupled receptor CRHR1 leads to transmembrane adenylyl cyclases stimulation with the consequent increase in intracellular cAMP. However, CRH signaling pathways are only partially understood, and the molecular components involved in the signal transduction largely depend on cellular context. We propose to explore CRHR1 signaling network in order to identify mechanisms critical for CRH action in the brain, with potential therapeutic relevance for stress-related disorders. Given the key role of CRH in the hippocampus, we have used the HT22 cell line as a neuronal hippocampal model to elucidate the molecular components of CRHR1 signaling pathways. For this project we propose to extend our knowledge of the CRH/CRHR1 system by two approaches. First, to investigate the existence of G-protein dependent and independent CRHR1-signaling mechanisms through a gene expression profiling strategy. Second, to evaluate the participation of a soluble adenylyl cyclase (sAC) as a second source of cAMP triggered by CRH in primary neuronal hippocampal cultures, as a highly physiological model. We have identified sAC as a potential B-Raf partner in a proteomic study performed in HT22 cells and we have shown a functional role of sAC in CRH signaling in HT22 and AtT20 cells. We anticipate that our results will be relevant to further understand the action of CRH during the stress response.