**3.4 TSHR-mAb induced signal transduction**

Through the stimulation of agonist, TSH and TSHR-Abs the TSH receptor seems to be active and enhanced. Intracellular signal transmissions spread through classical GPCR effector proteins with the Gαq and Gαs interaction with the recipient directly.

Docking Gαs into the activated receptor results in an increased adenylatecyclasis activity generated by the cAMP, direct activation of protein kinase A (PKA) and cAMP element-binding protein (CREB). Gαq docking involves PI3 and DAG formation and further activation of Ca2+ and protein kinase C (PKC). Enables Erk1/2 and p90RSK subsequently. Stimulating TSH-mAb has shown to act in a dose-dependent and time-dependent manner via the Gαq-PKC-Akt cascade, and the rat thyroid model (FrTL-5) was found to be relevant on PKA signaling [36, 37]. Monoclonal antibodies, which are frequently detected by point-of-care tests, were also demonstrated to activate non classical TSH receptor pathways, though this was reported as only a few of the studies have shown this. Certain neutral antibodies are not found to increase cAMP, but could signal by means of Akt, c-Raf/ERK1/2/p90RSK, PKC, and PKA/CREB [37].
