Agonist occupancy of a single monomeric element is sufficient to cause internalization of the dimeric β2-adrenoceptor

Growth Hormone Secretagogues and Growth Hormone Releasing Peptides Act As Orthosteric Super-Agonists but Not Allosteric Regulators for Activation of the G Protein Gαo1by the Ghrelin Receptor

“…This is intriguing because there are a growing number of instances in which ligands with highly selective affinity and/or potency for one GPCR can affect the pharmacology, function, and/or cellular distribution of a second GPCR for which they have no inherent direct affinity if the two GPCRs form a heterodimer (El-Asmar et al, 2005;Ellis et al, 2006;Parenty et al, 2008), and this has been discussed in terms of allosteric effects across the heterodimer interface (Milligan and Smith, 2007). However, such effects are substantially more challenging to explore for potential GPCR homo-dimers unless a mutated receptor, designed to alter its affinity to pharmacological agents, is paired with the corresponding wild-type receptor to generate an asymmetric homodimer or pseudo heterodimer that has distinct pharmacology at each protomer (Damian et al, 2006;Sartania et al, 2007).…”

G Protein–Coupled Receptor Multimers: A Question Still Open Despite the Use of Novel Approaches

“…In contrast, coexpression of the wild-type b 2 -AR with receptors activated solely by a synthetic ligand (i.e. RASSL) b 2 -AR mutant revealed that agonist stimulation of either protomer induced internalization of the dimer (Sartania et al, 2007). Altogether, a discrepancy in the transient nature of at least some GPCR dimers is observed between single molecule labeling strategies and studies demonstrating cointernalization and cotrafficking of receptors (Milligan, 2010).…”

Allostery at G Protein-Coupled Receptor Homo- and Heteromers: Uncharted Pharmacological Landscapes

“…Much information has been obtained from studies in which one or more protomers have been modified by mutation (Damian et al, 2006;Sartania et al, 2007;Alvarez-Curto et al, 2010b). Although we do not strictly adhere to the definitions above, for reasons of simplicity we will also refer to dimers in which such modifications have been made to the same receptor subtype as receptor homomers.…”

“…There is certainly evidence that binding of a single ligand to dimers may be sufficient to promote internalization and this may even be true for a homomer. An interesting means to explore this involved stable coexpression of wild-type ␤ 2 -adrenoceptor along with a form of this GPCR containing a point mutation (D 113 S) that greatly reduces the affinity/potency of isoprenaline but greatly increases the affinity/potency of the synthetic orthosteric agonist 1-(3Ј,4Ј-dihydroxyphenyl)-3-methyl-1-butanone (L158870), which does not bind to the wild-type receptor with significant affinity (Sartania et al, 2007). In cells coexpressing the two forms of the ␤ 2 -adrenoceptor, both isoprenaline and L158870 were able to promote internalization of both receptor variants because they produced a homomer (Sartania et al, 2007).…”