Different role of intracellular loops of glucagon-like peptide-1 receptor in G-protein coupling

Previous studies revealed the importance of the third intracellular loop of glucagon-like peptide-1 receptor (GLP-1R) in coupling to G(s) and G(i1) proteins. In order to further study the signaling mechanisms of GLP-1R, we tested three peptides, corresponding to the sequences of the first (IC1), the second (IC2), and the third (IC3) intracellular loop of GLP-1R, for their interactions with heterotrimeric G-proteins of different types (G(alphas), G(alphao), G(alphai1), and G(alpha11) plus G(beta1gamma2)) overexpressed in sf9 cells. IC3 peptide powerfully stimulates all types of tested G-proteins, whereas IC1 and IC2 peptides show differential effects on G-proteins. Both IC1 and IC2 peptides activate G(s) and cooperate with IC3 peptide in its stimulation. G(0) is not affected by IC1 and IC2. G(i1) and G(1I) are not affected by IC1, but are activated by IC2, which in activation cooperates with IC3. We suggest that GLP-1R is not coupled only to G(s) and G(i1), as shown previously, but also to G(0) and G(11). IC3 loop is the main switch that mediates signaling via GLP-1R to G-proteins, while IC1 and IC2 loops are important in discrimination between different types of G-proteins. (C) 2002 Elsevier Science B.V. All rights reserved.