Functional Water Channels Within the TSH Receptor - a new paradigm for TSH action with disease implications

Endocrinology. 2023 Sep 28:bqad146. doi: 10.1210/endocr/bqad146. Online ahead of print.ABSTRACTThe TSH receptor (TSHR) transmembrane domain (TMD) lives in the plasma membrane consisting of lipids and water molecules. To understand the role of TSHR-associated water molecules we used molecular dynamic simulations of the TMD and identified a network of putative receptor associated transmembrane water channels. This result was confirmed with extended simulations of the full length TSHR with and without TSH ligand binding. While the transport time observed in the simulations via the TSHR protein was slower than via the lipid bilayer itself we found that significantly more waters traversed via the TSHR than via the lipid bilayer which more than doubled with the binding of TSH. Using rat thyroid cells (FRTL-5) and a calcein fluorescence technique we measured cell volumes after blockade of aquaporins 1 and 4, the major thyroid cell water transporters. TSH showed a dose-dependent ability to influence water transport and similar effects were observed with stimulating TSHR autoantibodies. Small molecule TSHR agonists, which are allosteric activators of the TMD, also enhanced water transport illustrating the role of the TMD in this phenomenon. Furthermore, the water channel pathway was also mapped across two activation motifs within the TSHR TMD suggesting how water movement may influence activation of the receptor. In pathophysiological conditions such as hypothyroidism and hyperthyroid...
Source: Endocrinology - Category: Endocrinology Authors: Source Type: research