[Signal transduction of the thyrotropin receptor]

The thyrotropin receptor (TSHR) mediates dual signalling, cAMP and phosphoinositide (PIP2) responses. We have characterized the roles of the 2nd and 3rd cytoplasmic loops on signal transduction by site-directed mutagenesis. Middle portion in the 2nd loop (residues 525-527) is found to be important for Gs coupling. On the other hand, N- and C-terminal regions of the 3rd loop and residues 528-532 in the 2nd loop are important for Gq coupling. Further, mutations involving residue 617-620 in the 3rd loop result in constitutive activation. Constitutively activating mutations of the TSHR and LH/CGR (lutropin/choriogonadotropin receptor) are found in functional thyroid adenoma and familial male precocious puberty, respectively, and appear to be the direct cause of each disease.