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

Abstract

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 (IC 1), the second (IC 2), and the third (IC 3) intracellular loop of GLP-1R, for their interactions with heterotrimeric G-proteins of different types (G αs, G αo, G αi1, and G α11 plus G β1γ2) overexpressed in sf9 cells. IC 3 peptide powerfully stimulates all types of tested G-proteins, whereas IC 1 and IC 2 peptides show differential effects on G-proteins. Both IC 1 and IC 2 peptides activate G s and cooperate with IC 3 peptide in its stimulation. G o is not affected by IC 1 and IC 2. G i1 and G 11 are not affected by IC 1, but are activated by IC 2, which in activation cooperates with IC 3. We suggest that GLP-1R is not coupled only to G s and G i1, as shown previously, but also to G o and G 11. IC 3 loop is the main switch that mediates signaling via GLP-1R to G-proteins, while IC 1 and IC 2 loops are important in discrimination between different types of G-proteins.