Coexpressed class B G protein-coupled secretin and GLP-1 receptors self-and cross-associate: Impact on pancreatic islets

Class B guanine nucleotide-binding protein (G protein)-coupled receptors form symmetrical homodimeric complexes along the lipid face of transmembrane segment 4 (TM4) and can form heterodimeric complexes, although their structure is unknown. The current study demonstrates that the lipid face of TM4 is also the predominant determinant for formation of heteroreceptor complexes between two class B receptors, secretin receptor (SecR) and glucagonlike peptide-1 receptor (GLP-1R), which are expressed on pancreatic islet cells. Because these receptors use the same interface for formation of homo-and heteroreceptor complexes, competitive forces may affect expression of different complexes. Assessment of SecR and GLP-1R dimeric complexes via recombinant expression in Chinese hamster ovary cells revealed that homodimeric receptor complexes were more stable than the heterodimeric complexes, and the homodimeric SecR/SecR is more stable than the GLP-1R/GLP-1R complex. Given the greater tendency for homodimeric compared with heterodimeric complex formation, the heteroreceptor complexes lacked the expression that might have been predicted by geometry alone. Nevertheless, cells coexpressing these receptors formed heterodimeric complexes that correlated with reduced intracellular calcium responses to secretin, but no change in the cyclic adenosine monophosphate responses to each natural agonist. This functional effect was confirmed in pancreatic islets isolated from wild-type and GLP-1R knockout mice. In these cells, the increased calcium response mediated by secretin in the absence of GLP-1R was paralleled by an increased glucose-dependent insulin response, indicating that the heterodimeric receptor complexes modulate secretin responses. Furthermore, the heterodimeric receptor complexes also mediated agonist-induced cross-receptor internalization, a process that could have broad functional significance in sites of natural receptor coexpression.