Allosteric modulation in monomers and oligomers of a G protein-coupled receptor

Shivnaraine, Rabindra V.; Kelly, Brendan; Sankar, Krishana S.; Redka, Dar′ya S.; Han, Yi Rang; Huang, Fei; Elmslie, Gwendolynne; Pinto, Daniel O.; Li, Yuchong; Rocheleau, Jonathan V.; Gradinaru, Claudiu C.; Ellis, John E.; Wells, James W.

doi:10.7554/elife.11685

Cited by 23 publications

(29 citation statements)

References 27 publications

(72 reference statements)

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“…Communication between protomers resulting in asymmetric properties among receptor molecules within small oligomers such as dimers and tetramers has been documented for both rhodopsin and other GPCRs [25, 28, 76, 77]. For some GPCRs, this communication within a dimer or tetramer appears to play a central role in receptor signaling and underlies the efficacy of the system [78, 79].…”

Section: Discussionmentioning

confidence: 99%

Quaternary structures of opsin in live cells revealed by FRET spectrometry

Mishra

Gragg

Stoneman

et al. 2016

Biochemical Journal

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Rhodopsin is a prototypical G-protein coupled receptor (GPCR) that initiates phototransduction in the retina. The receptor consists of the apoprotein opsin covalently linked to the inverse agonist 11-cis retinal. Rhodopsin and opsin have been shown to form oligomers within the outer segment disc membranes of rod photoreceptor cells. However, the physiological relevance of the observed oligomers has been questioned since observations were made on samples prepared from the retina at low temperatures. To investigate the oligomeric status of opsin in live cells at body temperatures, we utilized a novel approach called FRET spectrometry, which previously has allowed the determination of the stoichiometry and geometry (i.e., quaternary structure) of various GPCRs. In the current study, we have extended the method to additionally determine whether or not a mixture of oligomeric forms of opsin exists and in what proportion. Application of this improved method revealed that opsin expressed in live Chinese hamster ovary (CHO) cells at 37 °C exists as oligomers of various sizes. At lower concentrations, opsin existed in an equilibrium of dimers and tetramers. The tetramers were in the shape of a near-rhombus. At higher concentrations of the receptor, higher order oligomers began to form. Thus, a mixture of different oligomeric forms of opsin is present in the membrane of live CHO cells and oligomerization occurs in a concentration-dependent manner. The general principles underlying the concentration-dependent oligomerization of opsin may be universal and apply to other GPCRs as well.

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Section: Discussionmentioning

confidence: 99%

Quaternary structures of opsin in live cells revealed by FRET spectrometry

Mishra

Gragg

Stoneman

et al. 2016

Biochemical Journal

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“…within the seven TM), whereas, in class C GPCR, the two sites are usually well separated (see Wu et al, 2014). When a receptor complex forms, the allosteric binding sites on single monomers may undergo structural and functional changes (see Shivnaraine et al, 2016). Of significant interest, however, is the possibility that, when the complex forms, the quaternary structure could display novel specific allosteric sites suitable for the binding of some modulator.…”

Section: Quaternary Structure Of Gpcr Complexesmentioning

confidence: 99%

G protein-coupled receptor-receptor interactions give integrative dynamics to intercellular communication

Guidolin

Marcoli

Tortorella

et al. 2018

Reviews in the Neurosciences

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Abstract:The proposal of receptor-receptor interactions (RRIs) in the early 1980s broadened the view on the role of G protein-coupled receptors (GPCR) in the dynamics of the intercellular communication. RRIs, indeed, allow GPCR to operate not only as monomers but also as receptor complexes, in which the integration of the incoming signals depends on the number, spatial arrangement, and order of activation of the protomers forming the complex. The main biochemical mechanisms controlling the functional interplay of GPCR in the receptor complexes are direct allosteric interactions between protomer domains. The formation of these macromolecular assemblies has several physiologic implications in terms of the modulation of the signaling pathways and interaction with other membrane proteins. It also impacts on the emerging field of connectomics, as it contributes to set and tune the synaptic strength. Furthermore, recent evidence suggests that the transfer of GPCR and GPCR complexes between cells via the exosome pathway could enable the target cells to recognize/decode transmitters and/or modulators for which they did not express the pertinent receptors. Thus, this process may also open the possibility of a new type of redeployment of neural circuits. The fundamental aspects of GPCR complex formation and function are the focus of the present review article.

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“…It has been shown that the presence of one protomer can alter membrane localization (Ellis et al, 2006;Rozenfeld et al, 2012), the affinity and/or efficacy of agonists (Martin and Prather, 2001;Rozenfeld et al, 2012;Wang et al, 2005), and signaling specificity (Charles et al, 2003;Rozenfeld et al, 2012) for the other promoter. Moreover, ligand binding to the orthosteric site of one promoter can change the pharmacological properties of orthosteric ligands for the other protomer (Ferre et al, 2016;Shivnaraine et al, 2016;Vischer et al, 2011). For example, apelin binding to its receptor reduces the binding and efficacy of angiotensin II acting at the angiotensin II Type 1 receptor via negative cooperativity between the protomers of the heteromer (Siddiquee et al, 2013).…”

Section: Introductionmentioning

confidence: 99%