Article

Preferences of transmembrane helices for cooperative amplification of Gαs and Gαq signaling of the thyrotropin receptor

III. Medical Department, University of Leipzig, Germany.
Cellular and Molecular Life Sciences CMLS (Impact Factor: 5.81). 12/2008; 65(24):4028-38. DOI: 10.1007/s00018-008-8530-3
Source: PubMed

ABSTRACT

The majority of constitutively activating mutations (CAMs) of the thyroid-stimulating hormone receptor display a partially activated receptor. Thus, full receptor activation requires a multiplex activation process. To define impacts of different transmembrane helices (TMHs) on cooperative signal transduction, we combined single CAMs in particular TMHs to double mutations and measured second messenger accumulation of the G(alpha)s and the G(alpha)q pathway. We observed a synergistic increase for basal activity of the G(alpha)s pathway, for all characterized double mutants except for two combinations. Each double mutation, containing CAMs in TMH2, 6 and 7 showed the highest constitutive activities, suggesting that these helices contribute most to G(alpha)s-mediated signaling. No single CAM revealed constitutive activity for the G(alpha)q pathway. The double mutations with CAMs from TMH1, 2, 3 and 6 also exhibited increase for basal G(alpha)q signaling. Our results suggest that TMH2, 6, 7 show selective preferences towards G(alpha)s signaling, and TMH1, 2, 3, 6 for G(alpha)q signaling.

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    • "Several mutations identified by mutagenesis studies (L417V, TMH1 [64]; S562A, ECL2 [64]; Y605A, TMH5 [41]; N658A, ECL3 [65]) of the TSHR are characterized by the same functional finding. By simultaneous combination of CAMs in the TSHR it was recently shown that the transmembrane helices are characterized by different preferences for cooperative amplification of Gs and Gq mediated signaling pathways [66]. These examples indicate that for full and multiple GPHR activation in terms of dual Gs and Gq coupling, highly specific structural conformations of the intracellular region must be induced by the entire receptor protein. "
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