TSH Receptor Autoregulation

ABSTRACT The thyroid stimulating hormone receptor (TSHR) is the major control center of the thyroid cell and the target of autoimmune thyroid disease. The TSHR is a GPCR on the thyroid cell but is not confined to the thyroid since it has widespread extrathyroidal expression in fibroblasts, adipocytes, bone cells and brain tanycytes where they are presumably associated with unique roles. Recently, using Molecular Dynamic (MD) simulation studies we identified water channels within the TSHR transmembrane domain (TMD). Furthermore, using an in vitro assay of water transport in thyrocytes, we have shown that receptor activation with TSH ligand, TSHR specific small molecules and TSHR stimulating antibodies all enhanced water flow. In this proposal we intend to examine the mechanism of TSHR water transport and its link to receptor signaling, discover novel small molecules that can modulate this water transport leading to physiological changes and marry these observations to translational effects on brain hypothalamic tanycytes. Therefore, the specific aims are: Aim 1: How is water transported within the TSHR- TMD water channels and does water passage affect TSHR signaling? Aim 2: Can we identify novel TSHR specific small molecules that influence water transport? Aim 3: Does the TSHR water channel influence hypothalamic tanycyte actions? These studies will determine if modulation of TSHR signaling in the thyroid cell and many other extra-thyroidal sites is secondary to water channel function and may perturb cellular homeostasis.