Evidence for the direct involvement of transmembrane region 6 of the lutropin/choriogonadotropin receptor in activating G(S)

The luteinizing hormone/chorionic gonadotropin receptor (LHR) is a heptahelical receptor that interacts primarily with G(s). Previous studies by others have shown that some forms of familial male precocious puberty are associated with mutations of the human LHR in the sixth transmembrane region that result in constitutive activation of the receptor. This study demonstrates that a peptide corresponding to the lower portion of the sixth transmembrane region of the LHR can significantly activate adenylyl cyclase activity. Experiments with membranes derived from wild-type versus cyc(-) S49 cells demonstrate that the stimulation of cyclase by this peptide is due to an activation of G(s). As such, our data demonstrate a direct role for transmembrane region 6 of the rat LHR in activating G(s) and therefore raise the possibility that mutations in transmembrane region 6 of the LHR may directly affect the coupling of the receptor to G(s). Significantly, these data are the first to demonstrate the ability of a transmembrane portion of a G protein-coupled receptor, in the absence of any contributions from an intracellular loop region, to activate a G protein.