The Role of the Cell Background in Biased Signaling

Romero, Guillermo

doi:10.1016/b978-0-12-411460-9.00002-1

Cited by 2 publications

(6 citation statements)

References 169 publications

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“…In addition [see (187)], increasing evidence has shown that responses to specific ligands are critically influenced by the environment in which receptors and receptor complexes are located, and, in particular, by other proteins and biochemical constituents that establish structural or functional interactions with them. Within this context, signaling cannot be viewed exclusively as the output of a single receptor-agonist pair; rather, it often results from the modification of the targeted receptor or receptor complex by scaffolding proteins and other signaling partners.…”

Section: Discussionmentioning

confidence: 99%

“…Thus, when RRI take place at the membrane, the actual signaling outcomes of receptor complexes depend on several factors, including the composition of the complex and its topological organization, the traffic of the receptor complex, the effects of ligands on the formation of the assembly and on its stability, and, quite often, crosstalk with alternative signaling pathways (48, 187). Together, these factors may strongly influence the chain of events linking ligand recognition to signal transduction from the single protomers.…”

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

“…These can be briefly summarized as follows [see (187) and, with regard to GPCRs, (7, 8, 28, 53) for reviews]: In a variety of receptor complexes, modulation of the binding sites has been reported as a consequence of allosteric RRI. One of the first examples was the A 2A -D 2 heterodimer, where the binding of the adenosine A 2A agonist CGS21680 reduced the affinity of the dopamine D 2 agonist-binding site (188).…”

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

“…IR and the closely related insulin-like growth factor receptor 1 (IGF 1 ) are present in the membrane as preformed dimeric complexes, and both bind insulin and members of the insulin-like peptide family. Signaling through IR and IGF 1 , however, has different physiological outcomes [see (187)], with IGF 1 signaling being essentially mitogenic (through the Ras/MAPK pathway) and IR signaling mainly producing metabolic effects (through the PDK/Akt pathway). The EGFR provides a further example.…”

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

“…A final aspect that deserves to be mentioned [see (8, 187) for a more detailed discussion] is the cell environment in which receptors and receptor complexes are located. Indeed, their signaling outcome is also influenced by the network of molecular interactions they can establish with other biochemical components.…”

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

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Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

et al. 2019

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The discovery of receptor-receptor interactions (RRI) has expanded our understanding of the role that G protein-coupled receptors (GPCRs) play in intercellular communication. The finding that GPCRs can operate as receptor complexes, and not only as monomers, suggests that several different incoming signals could already be integrated at the plasma membrane level via direct allosteric interactions between the protomers that form the complex. Most research in this field has focused on neuronal populations and has led to the identification of a large number of RRI. However, RRI have been seen to occur not only in neurons but also in astrocytes and, outside the central nervous system, in cells of the cardiovascular and endocrine systems and in cancer cells. Furthermore, RRI involving the formation of macromolecular complexes are not limited to GPCRs, being also observed in other families of receptors. Thus, RRI appear as a widespread phenomenon and oligomerization as a common mechanism for receptor function and regulation. The discovery of these macromolecular assemblies may well have a major impact on pharmacology. Indeed, the formation of receptor complexes significantly broadens the spectrum of mechanisms available to receptors for recognition and signaling, which may be implemented through modulation of the binding sites of the adjacent protomers and of their signal transduction features. In this context, the possible appearance of novel allosteric sites in the receptor complex structure may be of particular relevance. Thus, the existence of RRI offers the possibility of new therapeutic approaches, and novel pharmacological strategies for disease treatment have already been proposed. Several challenges, however, remain. These include the accurate characterization of the role that the receptor complexes identified so far play in pathological conditions and the development of ligands specific to given receptor complexes, in order to efficiently exploit the pharmacological properties of these complexes.

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Section: Discussionmentioning

confidence: 99%

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

Section: Pharmacological Features Of the Receptor Complexesmentioning

confidence: 99%

See 3 more Smart Citations

Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

et al. 2019

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Receptor–Receptor Interactions and Glial Cell Functions with a Special Focus on G Protein-Coupled Receptors

Guidolin

Tortorella

Marcoli

et al. 2021

IJMS

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The discovery that receptors from all families can establish allosteric receptor–receptor interactions and variably associate to form receptor complexes operating as integrative input units endowed with a high functional and structural plasticity has expanded our understanding of intercellular communication. Regarding the nervous system, most research in the field has focused on neuronal populations and has led to the identification of many receptor complexes representing an important mechanism to fine-tune synaptic efficiency. Receptor–receptor interactions, however, also modulate glia–neuron and glia–glia intercellular communication, with significant consequences on synaptic activity and brain network plasticity. The research on this topic is probably still at the beginning and, here, available evidence will be reviewed and discussed. It may also be of potential interest from a pharmacological standpoint, opening the possibility to explore, inter alia, glia-based neuroprotective therapeutic strategies.

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The Role of the Cell Background in Biased Signaling

Cited by 2 publications

References 169 publications

Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

Receptor-Receptor Interactions as a Widespread Phenomenon: Novel Targets for Drug Development?

Receptor–Receptor Interactions and Glial Cell Functions with a Special Focus on G Protein-Coupled Receptors

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