G protein-coupled receptors (GPCRs) are membrane-bound proteins that sense external stimuli and relay signals inside the cell, resulting in various physiological outcomes. While GPCRs can exist as monomers, some types, like class C GPCRs, are obligate dimers, either as homodimers or heterodimers, with distinct conformations in both their inactive and active states [1, 2]. The possibility of dimerization in class A and class B GPCRs, however, has been more controversial, despite increasing evidence that these receptors can also form dimers. These dimeric forms, which can either be transient or stable, are believed to influence the function and regulation of GPCRs—a process known as receptor cross-talk [3]. For example, dimerization has been shown to affect signaling pathways in class A dopamine receptors like D1/D2 and D1/D3, which exhibit distinct pharmacological profiles in their dimeric form compared to their monomeric counterparts [4].
Class B1 GPCRs are an important subclass of GPCRs that include 15 receptors involved in regulating body homeostasis and metabolism, and they are activated by peptide hormones [5]. Recent studies suggest that class B1 GPCRs can form both homodimers and heterodimers, which may play a crucial role in modulating receptor function and ligand signaling. These dimeric interactions may contribute to the phenomenon of biased agonism, where ligands produce different signaling outcomes depending on the receptor conformation or dimerization state. Examples of class B1 GPCRs forming homodimers include the secretin receptor (SecR)[6] and GLP-1R [7], while GLP-1R is also known to heterodimerize with the GIPR in recombinant cell system [8].
Research using techniques like bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET) has revealed that GLP-1R homodimerization occurs via transmembrane helix 4 (TM4), which forms the interface for both homo- and heterodimers [9]. These studies also show that disrupting the dimerization of GLP-1R results in decreased high-affinity binding to its natural ligand, GLP-1, while selectively affecting receptor signaling. Such findings suggest that dimerization is critical for regulating GPCR function, particularly with respect to biased agonism, which may alter downstream signaling outcomes based on the receptor's dimeric state.
One of the most intriguing examples of class B1 GPCR dimerization involves the secretin receptor (SecR). SecR dimerization enhances the receptor’s signaling efficiency by increasing its dynamics in a G protein-dependent manner [6]. This dimerization allows the N-terminal activation domain of the receptor to repeatedly engage and disengage from the receptor’s core, which is crucial for G protein recruitment. As a result, dimerized SecR receptors exhibit higher rates of G protein activation and release, improving both binding affinity and signaling potency. Additionally, the dimeric state allows rotational movement of the receptor's extracellular domain (ECD), facilitating the partial disengagement of the peptide while maintaining high-potency signaling.
In summary, dimerization in class B1 GPCRs is an emerging area of research that has far-reaching implications for our understanding of GPCR function and signal transduction. While class B1 GPCRs were initially thought to function primarily as monomers, mounting evidence suggests that their ability to form dimers—whether homodimers or heterodimers—plays a critical role in regulating receptor function, ligand binding, and downstream signaling. This insight not only enhances our understanding of class B1 GPCR biology but also opens new avenues for developing therapeutic agents that target specific receptor dimer states to modulate signaling in diseases related to metabolism and homeostasis.
References
1. Gusach, A., J. García-Nafría, and C.G. Tate, New insights into GPCR coupling and dimerisation from cryo-EM structures. Current Opinion in Structural Biology, 2023. 80: p. 102574.
2. Bouvier, M., Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci, 2001. 2(4): p. 274-86.
3. Guo, W., et al., Crosstalk in G protein-coupled receptors: Changes at the transmembrane homodimer interface determine activation. Proceedings of the National Academy of Sciences, 2005. 102(48): p. 17495-17500.
4. Perreault, M.L., et al., Heteromeric dopamine receptor signaling complexes: emerging neurobiology and disease relevance. Neuropsychopharmacology, 2014. 39(1): p. 156-68.
5. Graaf, C., et al., Glucagon-Like Peptide-1 and Its Class B G Protein-Coupled Receptors: A Long March to Therapeutic Successes. Pharmacol Rev, 2016. 68(4): p. 954-1013.
6. Harikumar, K.G., et al., Impact of secretin receptor homo-dimerization on natural ligand binding. Nature Communications, 2024. 15(1): p. 4390.
7. Harikumar, K.G., et al., Glucagon-like peptide-1 receptor dimerization differentially regulates agonist signaling but does not affect small molecule allostery. Proc Natl Acad Sci U S A, 2012. 109(45): p. 18607-12.
8. Schelshorn, D., et al., Lateral allosterism in the glucagon receptor family: glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation. Mol Pharmacol, 2012. 81(3): p. 309-18.
9. Wootten, D., et al., Allostery and Biased Agonism at Class B G Protein-Coupled Receptors. Chem Rev, 2017. 117(1): p. 111-138.
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