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Class B GPCRs form symmetrical homo-dimeric complexes along the lipid face of transmembrane segment 4, and can form hetero-dimeric complexes, although their structure is unknown. The current study demonstrates that the lipid face of TM4 is also the predominant determinant for formation of hetero-receptor complexes between two class B receptors, secretin receptor (SecR) and glucagon-like peptide-1 receptor (GLP-1R), expressed on pancreatic islet cells. Since these receptors use the same interface for formation of homo- and hetero-receptor complexes, there might be competitive forces affecting expression of different complexes. Assessment of SecR and GLP-1R dimeric complexes via recombinant expression in CHO cells revealed that homo-dimeric receptor complexes were more stable than the hetero-dimeric complex, with homo-dimeric SecR/SecR more stable than GLP-1R/GLP-1R. Because of greater tendency to form homo-dimeric over hetero-dimeric complexes, detection of the hetero-receptor complexes lagged the expression that might have been predicted by geometry alone. Nevertheless, cells co-expressing these receptors did form hetero-dimeric complexes that correlated with reduced intracellular calcium responses to secretin, but no change in the cAMP 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 the GLP-1R was paralleled by an increased glucose-dependent insulin response, indicating that the hetero-dimeric receptor complexes modulate secretin responses. Furthermore, the hetero-dimeric receptor complexes also mediated agonist-induced cross-receptor internalization, a process that could have broad functional significance in sites of natural receptor co-expression.
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