G-protein-coupled receptor type A heteromers as an emerging therapeutic target

Guidolin, Diego; Agnati, Luigi F.; Marcoli, Manuela; Borroto-Escuela, Dasiel O.

doi:10.1517/14728222.2014.981155

Cited by 40 publications

(47 citation statements)

References 171 publications

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“…The vast majority of subsequent investigations, although each characterized by points of strength and weakness, provided consistent evidence in support of this proposal (see Milligan, 2009;Guidolin et al, 2015;Farran, 2017, for reviews) and the need for a broader view on intercellular communication. Indeed, allosteric RRI made possible through receptor oligomerization may lead to novel receptor dynamics during which the receptor protomers change their recognition, pharmacology, signaling, and trafficking and novel allosteric binding sites can develop (Agnati et al, 2010b;Fuxe et al, 2012;Fuxe and Borroto-Escuela, 2016).…”

Section: Discussionmentioning

confidence: 76%

“…Homodimers are pairs of the same protomer, whereas heterodimers are formed from distinct GPCR. The number of described homodimers and heterodimers in both cellular systems and native tissues is at present very high (see Fuxe et al, 2015;Guidolin et al, 2015;Borroto-Escuela et al, 2017; Farran, 2017, for reviews), and Table 1 only provides some example. However, the evidence that a GPCR can exploit multiple interaction interfaces can significantly influence the architecture of the resulting receptor complexes in at least two aspects: -The first concerns the stoichiometry of the complex (i.e.…”

Section: Quaternary Structure Of Gpcr Complexesmentioning

confidence: 99%

“…They can be briefly summarized as follows (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for more specific reviews): -Modulation of the binding sites has been reported to occur in a variety of RM 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 CGS-21680 lead to a reduction of the affinity of the high-affinity dopamine D 2 agonist binding site (Fuxe et al, 1998).…”

Section: Rm and Vmnsmentioning

confidence: 99%

“…The amount of data supporting the existence of GPCR heteromers showed a huge increase as far as biophysical techniques capable of detecting the spatial proximity of protein molecules were developed and became widespread (Bai, 2004;Guidolin et al, 2015). Biological methods for identifying GPCR oligomers in cells and tissues or in recombinant mammalian expression systems presently include energy transfer-based methods [fluorescence resonance energy transfer (FRET) and bioluminescence resonance energy transfer (BRET); Fernandez-Dueñas et al, 2012], bimolecular luminescence or fluorescence complementation (Gandia et al, 2008), total internal reflection fluorescence microscopy (Hern et al, 2010), fluorescence correlation spectroscopy (Chen et al, 2003), analysis of colocalization in immunohistochemical preparations (Agnati et al, 2005a), coimmunoprecipitation , assays based on bivalent ligands (Yekkirala et al, 2013), and in situ proximity ligation assays (Trifilieff et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

“…This aspect is presently the subject of intense research (see Guidolin et al, 2015;Borroto-Escuela et al, 2017;Farran, 2017, for recent reviews). In recent years, such an effort allowed the characterization of a panel of receptor complexes representing possible targets for the treatment of pathologic conditions, such as Parkinson's disease , schizophrenia and depression Sahlholm et al, 2017), neuropathic pain , addiction (Gomes et al, 2013), and food intake disorders (Kern et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 76%

Section: Quaternary Structure Of Gpcr Complexesmentioning

confidence: 99%

Section: Rm and Vmnsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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Does a Self-Similarity Logic Shape the Organization of the Nervous System?

Guidolin¹,

Tortorella²,

De³

et al. 2016

Springer Series in Computational Neuroscience

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From the morphological point of view, the nervous system exhibits a fractal, self-similar geometry at various levels of observations, from single cells up\ud to cell networks. From the functional point of view, it is characterized by a hierarchic organization in which self-similar structures (networks) of different miniaturizations\ud are nested within each other. In particular, neuronal networks, interconnected to form neuronal systems, are formed by neurons, which operate thanks to their\ud molecular networks, mainly having proteins as components that via protein–protein interactions can be assembled in multimeric complexes working as micro-devices.\ud On this basis, the term “self-similarity logic” was introduced to describe a nested organization where at the various levels almost the same rules (logic) to perform\ud operations are used. Self-similarity and self-similarity logic appear intimately linked to the biophysical evidence for the nervous system being a pattern-forming\ud system that can switch fl exibly from one coherent state to another. Thus, they can represent key concepts to describe its complexity and its concerted, holistic\ud behavior

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Protein–Protein Docking in Drug Design and Discovery

Kaczor

Bartuzi

Stępniewski

et al. 2018

Methods in Molecular Biology

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Protein-protein interactions (PPIs) are responsible for a number of key physiological processes in the living cells and underlie the pathomechanism of many diseases. Nowadays, along with the concept of so-called "hot spots" in protein-protein interactions, which are well-defined interface regions responsible for most of the binding energy, these interfaces can be targeted with modulators. In order to apply structure-based design techniques to design PPIs modulators, a three-dimensional structure of protein complex has to be available. In this context in silico approaches, in particular protein-protein docking, are a valuable complement to experimental methods for elucidating 3D structure of protein complexes. Protein-protein docking is easy to use and does not require significant computer resources and time (in contrast to molecular dynamics) and it results in 3D structure of a protein complex (in contrast to sequence-based methods of predicting binding interfaces). However, protein-protein docking cannot address all the aspects of protein dynamics, in particular the global conformational changes during protein complex formation. In spite of this fact, protein-protein docking is widely used to model complexes of water-soluble proteins and less commonly to predict structures of transmembrane protein assemblies, including dimers and oligomers of G protein-coupled receptors (GPCRs). In this chapter we review the principles of protein-protein docking, available algorithms and software and discuss the recent examples, benefits, and drawbacks of protein-protein docking application to water-soluble proteins, membrane anchoring and transmembrane proteins, including GPCRs.

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G-protein-coupled receptor type A heteromers as an emerging therapeutic target

Cited by 40 publications

References 171 publications

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

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

Does a Self-Similarity Logic Shape the Organization of the Nervous System?

Protein–Protein Docking in Drug Design and Discovery

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