Receptor Oligomerization in Family B1 of G-Protein-Coupled Receptors: Focus on BRET Investigations and the Link between GPCR Oligomerization and Binding Cooperativity

Abstract

The superfamily of the seven transmembrane G-protein-coupled receptors (7TM/GPCRs) is the largest family of membrane-associated receptors. GPCRs are involved in the pathophysiology of numerous human diseases, and they constitute an estimated 30–40% of all drug targets. During the last two decades, GPCR oligomerization has been extensively studied using methods like bioluminescence resonance energy transfer (BRET) and today, receptor–receptor interactions within the GPCR superfamily is a well-established phenomenon. Evidence of the impact of GPCR oligomerization on, e.g., ligand binding, receptor expression, and signal transduction indicates the physiological and pharmacological importance of these receptor interactions. In contrast to the larger and more thoroughly studied GPCR subfamilies A and C, the B1 subfamily is small and comprises only 15 members, including, e.g., the secretin receptor, the glucagon receptor, and the receptors for parathyroid hormone (PTHR1 and PTHR2). The dysregulation of several family B1 receptors is involved in diseases, such as diabetes, chronic inflammation, and osteoporosis which underlines the pathophysiological importance of this GPCR subfamily. In spite of this, investigation of family B1 receptor oligomerization and especially its pharmacological importance is still at an early stage. Even though GPCR oligomerization is a well-established phenomenon, there is a need for more investigations providing a direct link between these interactions and receptor functionality in family B1 GPCRs. One example of the functional effects of GPCR oligomerization is the facilitation of allosterism including cooperativity in ligand binding to GPCRs. Here, we review the currently available data on family B1 GPCR homo- and heteromerization, mainly based on BRET investigations. Furthermore, we cover the functional influence of oligomerization on ligand binding as well as the link between oligomerization and binding cooperativity.

The N-Terminal HSDCIF Motif Is Required for Cell Surface Trafficking and Dimerization of Family B G Protein Coupled Receptor PAC1

“…A similar finding contradictory to most studies showing PACAP increased cell survival reported that PACAP enhanced the oxidative stress induced cell death of human choriocarcinoma cells [34]. As we known, the status of receptor such as externalization or internalization, oligmerization or not can alter the cells signals and the physiological functions of GPCR [6], [7], [8], [9]. The cell signals and consequent function induced by the exogenous oligopeptide HSDCIF were obviously different from that induced by PACAP.…”

“…Recently, it has been shown that the dimerization or oligomerization of GPCR may affect the physiological and pharmacological profiles of GPCR, such as trafficking of newly synthesized receptors to the cell surface, allosteric modulation of ligand binding, signaling specificity, co-internalization, or cross-inhibition of GPCRs. [6], [7], [8], [9]. Furthermore the secretin receptor, VPAC1 and VPAC2, which also are members of class B GPCR and have close relationship with PAC1, have been reported to form oligomerization (homo- or hetero-) [10], [11], [12].…”

Functional Consequences of Glucagon-like Peptide-1 Receptor Cross-talk and Trafficking

“…Heteromerization between GLP-1R and the closely related GIPR has been reported to result in cross-talk with functional consequences for GLP-1R signaling (16,17). In addition, heteromerization between GLP-1R and GCGR has been described (18). Because GLP-1R, GCGR, and GIPR are all (i) members of the family B 7TM/GPCRs based on their structural and sequential similarity, (ii) involved in blood glucose homeostasis regulation, and (iii) expressed in pancreatic islets (3), a functional cross-talk between these receptors could be anticipated.…”

New aspects of the C5a receptor

“…Cook's and Hagemann's groups discuss the possibility of an interaction of a homo-polymer formation not only with the C5aR but also with the C5aR ligand [25]. The idea may lead to a correct answer about various signal transduction pathways mediated by the C5aR.…”