GPCR heterodimers: asymmetries in ligand binding and signalling output offer new targets for drug discovery

Abstract

Dimers of GPCRs have held the imagination of researchers for almost 20 years. However, only recently has their value as potentially novel drug targets been increased significantly, and primarily, in the context of GPCR heterodimers. The view of receptor heterodimers as allosteric machines has transformed the way we understand structural and functional asymmetries inherent in their organization. These asymmetries alter both signalling output and how they might be targeted pharmacologically. The paper in this issue of BJP by Siddiquee and colleagues (2013) highlights our growing understanding of such asymmetries and their implications. They show that heterodimers of the angiotensin II AT1 receptor and the apelin receptor recognize and respond to their respective ligands in distinct ways from the parent receptors expressed alone. Further, they demonstrate asymmetric allosteric effects in the context of the heterodimer that may have significant implications for our understanding of such receptor complexes.

Conformational biosensors reveal allosteric interactions between heterodimeric AT1 angiotensin and prostaglandin F2α receptors

“…This could represent a coupling preference of the heterodimer or it may be possible that our biosensors are sensitive to conformations driven by particular G proteins coupled to the heterodimer. Capitalizing on such signal bias and asymmetric conformational crosstalk may provide novel venues for targeting heterodimers, ignored in most current drug discovery programs (57)(58)(59). As we have demonstrated previously, ligand binding to AT1R can modulate the functional output of FP (38).…”

Interaction between Angiotensin Receptor and β-Adrenergic Receptor Regulates the Production of Amyloid β-Protein

“…Since the oxidation or glycation of membrane proteins or lipids is known to progress with aging, 25,26) these changes, directly or indirectly, could cause the promotion of the heterodimerization or crosstalk of AT 1 R and β 2 -AR, which leads to the stimulation of Aβ production. It is also worth noting that there are many GPCR family members in the brain, including serotonin receptors, dopamine receptors and opioid receptors, 11) and that there are many medicines targeting these GPCRs including A, AT 1 R-deficient fibroblasts overexpressing APP were cultured with ICI or Prop in the presence or absence of Telm for 72 h. Aβ level in the cultured medium was measured with ELISA. Data were the average of four independent experiments.…”

“…10) Surprisingly, over 90% of GPCRs are expressed in the brain, where they appear to have important roles including cognition, mood, synaptic transmission and so on. 11) In addition, GPCRs, classically considered to function as monomers, are actually organized as homodimers and heterodimerize with other GPCR family members. 12) A growing number of observations demonstrate that GPCR oligomerization may occur in native tissues and may have important consequences in receptor function.…”

Prostaglandin FP receptor antagonists: discovery, pharmacological characterization and therapeutic utility

“…The discovery of the phenomenon of receptor dimerization and crosstalk between heterologous receptors has opened potential new avenues for novel drug discovery and treatment of diseases (Rozenfeld and Devi, ). Such allosteric functional interactions amongst FP receptors and angiotensin‐II (AT) receptors (AT 1 sub‐type) by formation of receptor dimers have been recently described (Goupil et al, , ). Here, AL‐8810 (FP receptor antagonist) and AS604872 (allosteric inhibitor; see above) produced trans‐inhibition of IPs production in A7r5 cells and antagonized mouse aortic contraction induced by either angiontensin II or PGF 2α (Goupil et al, ).…”