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Transmembrane domains of GPCR dimers – a novel hot spot for drug discovery

Transmembrane domains of GPCR dimers – a novel hot spot for drug discovery

G-protein-coupled receptors (GPCRs) can form biologically active homodimers or heterodimers which drive specific signaling pathways that can modulate both physiological and pathological functions. GPCR dimers are therefore emerging drug targets in different therapeutic areas including depression, hypertension, diabetes, and vascular dementia (A. Faron-Gorecka, et al. 2019). In this study Xin Cai et al. highlight the importance of GPCR dimers in drug discovery referring to important conformational changes, allosteric properties, ligand and functional selectivity.


But what are the conformation changes that drive GPCR dimerization? The interaction between two receptors in a dimer involves a conformational change in the transmembrane domain (TMD), with the most compelling studies revealing that the transmembrane helices TM4 and TM5 on one hand, and TM1 and TM7 on the other hand, form possible dimerization interfaces (Ploier, B. et al. 2016; Dijkman, P. M. et al. 2018; Manglik, A. et al. 2012). Interestingly, the amplitude of the conformational changes due to ligand binding is limited at these interfaces. An important example of a GPCR forming both monomers and dimers with distinct functions in respect to ligand binding, receptor activation, desensitization and trafficking is the apelin receptor (APJ) (Y. Li, et al 2012; B. Bai, et al. 2014; B. Ji, et al. 2020; L. Wan, 2020). APJ receptors form both homodimers and heterodimers with other members of the class A GPCR family such as with bradykinin 1 and 2 receptors (B. Bai et al. 2014; B. Ji et al., 2020).

GPCR dimers are very attractive molecular entities since they have been found to drive biased signalling. Various studies reported that the biased properties of ligands and receptors are a consequence of GPCR dimer formation, where the dimer corresponds to the biased receptor. Junke Liu et al. recently provided key insights into GPCR oligomerization and biased signalling, using PAFR as a model, showing that stabilization of PAFR oligomers promotes G protein activity, and decreases β-arrestin recruitment and agonist-induced internalization significantly.


How dynamic are GPCRs dimer interfaces? GPCRs constantly bind to form dimers and dissociate to form monomers. GPCRs dimers exist in a transient state however they are still able to be activated and interact with G proteins and therefore preserve their physiological functions, an important observation when considering them as potential targets. Different models of dimer formation have been described for different receptors such as the ‘rolling dimer’ interface model in which multiple dimer conformations co-exist and interconvert (P.M. Dijkman et al., 2018). Structural insights into metabotropic glutamate receptors have shown that the dimerization interface is affected by the activation state of the receptors, with the interface mainly located at TM4 and TM5 when mGluR2 dimers are inactive, switching to an interface mainly at TM6 when the receptor is active (L. Xue, et al. 2015).


What is the potential of targeting GPCR dimer interface in drug discovery? GPCR drugs efficacy usually depends on a pathway (G protein or β-arrestin), whereas side effects are normally mediated by another pathway (I. Mantas et al. 2022). Therefore, the biased properties of GPCR dimers comprise an opportunity to boost efficacy while reducing side effects.


But how can we target GPCR dimers? Recent studies found that peptides derived from the transmembrane region of GPCRs can block the formation of dimers and alter their function by destroying the interface between two receptors (M. Gallo et al. 2022). An example is a peptide derived from TM5/TM6 of the cannabinoid CB1 receptor (CB1R) which has been shown to alter the structure of CB1R–5HT2AR heterodimers, preventing cognitive impairment while preserving analgesia in vivo (M. Gallo et al. 2021).

A more in-depth analysis of the functional specificity of transmembrane peptides will provide a better understanding of the physiopathological role of GPCRs dimerization while accelerating drug discovery targeting GPCR dimers.


#GPCR #DrGPCR#Ecosystem



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