FIGURE 5-34 Posttranslational processing of /3-endorphin in rat intermediate pituitary. Reproduced with permission from Eipper, B. A., and Mains, R. E. (1981). }. Biol. Chem. 256, 5689-5695.

the activities of various domains. Thus, antibodies are available that stimulate cAMP levels or block the binding of TSH at different locations on the receptor molecule. Residues on the C-terminal region of the extracellular domain were found to be important for TSH binding. Cysteine residues at 301 and 380 (Figure 535) were critical for TSH binding. Residues 303-382 have low homology to gonadotropin receptors, and this region can be deleted without the loss of TSH binding or function. There are cysteine residues in the transmembrane domain that function in linking to a G-protein interaction site. By transfection, the TSH receptor has been shown to affect both cAMP and phos-phatidylinositol pathway (PIP2) responses in cells. Dual coupling is also a feature of the LH/ CG receptor in transfected cells. Mutation of alanine 623 of TSHR produces a loss in the TSH-stimulated PI cycle but not cAMP enhancement. Either one receptor is coupled to two pathways or two TSH receptors are in different conformations where one couples to cAMP and the other to the PI cycle. This possibility is shown in Figure 5-35.

Interaction of TSH with TSHR results in a conformational change in the receptor that enables the interaction of receptor and G proteins. This mechanism is suggested in Figure 5-36. Note that the a-subunit, in this model, interacts with the transmembrane domain. The effective portion of the a-subunit, perhaps similar to oxytocin or vasopressin, interacts with the transmembrane domain and G-protein interaction sites.

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