Read PDF G Protein Coupled Receptors: Trafficking and Oligomerization

Free download. Book file PDF easily for everyone and every device. You can download and read online G Protein Coupled Receptors: Trafficking and Oligomerization file PDF Book only if you are registered here. And also you can download or read online all Book PDF file that related with G Protein Coupled Receptors: Trafficking and Oligomerization book. Happy reading G Protein Coupled Receptors: Trafficking and Oligomerization Bookeveryone. Download file Free Book PDF G Protein Coupled Receptors: Trafficking and Oligomerization at Complete PDF Library. This Book have some digital formats such us :paperbook, ebook, kindle, epub, fb2 and another formats. Here is The CompletePDF Book Library. It's free to register here to get Book file PDF G Protein Coupled Receptors: Trafficking and Oligomerization Pocket Guide.

In summary, evidence obtained with a wide range of different methods is accumulating, which suggest that GPCRs function as dimers or oligomers. Although individual evidences can be, and most of them were, challenged based on methodical grounds, the multitude of available positive data suggest that some kind of dimerization, oligomerization, or clustering of most GPCRs does occur. However, it is apparently very difficult to obtain decisive evidence, whether these receptors are organized into well-defined structures, such as dimers or oligomers, and interact directly; or function in larger molecular complexes, where propagation of the information occurs via complex molecular networks.

It is likely that this issue will not be fully resolved until the necessary tools are developed to obtain high-resolution snapshots of GPCRs in their native environment. Although it may take a lot more time for structural biologists to achieve this goal, dimerization, or oligomerization of GPCRs is a very useful paradigm for pharmacologists to study properties of receptors, which require functionally important clustering, such as allosteric modulation of ligand binding, co-internalization, altered signaling properties, or cross-inhibition.

An elucidation of these interactions is an important immediate task since these are critical to understand the pharmacological effects of drugs targeted to receptors and to elucidate the physiological mechanism of action of hormones and other mediators that target GPCRs. The authors declare that there is no conflict of interest that would prejudice the impartiality of the present work.

Medical Biology 60 — Journal of Virology 78 — PNAS 97 — Analytical Biochemistry 77 — Molecular Pharmacology 67 — Journal of Biological Chemistry — Molecular Pharmacology 66 — Journal of Pharmacology and Experimental Therapeutics — Journal of Molecular Biology — Circulation — New England Journal of Medicine — EMBO Journal 18 — Biochemical Society Transactions 32 — Trends in Pharmacological Sciences 23 — Bouvier M Oligomerization of G-protein-coupled transmitter receptors.

Nature Reviews. Neuroscience 2 — Nature Methods 4 3 — 4. Breitwieser GE G protein-coupled receptor oligomerization: implications for G protein activation and cell signaling. Circulation Research 94 17 — Bulenger S Marullo S Bouvier M Emerging role of homo- and heterodimerization in G-protein-coupled receptor biosynthesis and maturation. Trends in Pharmacological Sciences 26 — Human Molecular Genetics 14 — Annual Review of Physiology 39 — Biochemistry 44 — Nature 30 — Science — Trends in Biotechnology 23 — Annals of the New York Academy of Sciences — Nature — Rate monitored by fluorescence resonance energy transfer.

Biophysical Journal 94 — Cvejic S Devi LA Dimerization of the delta opioid receptor: implication for a role in receptor internalization. PNAS 74 — Dell'Orco D Seeber M Fanelli F Monomeric dark rhodopsin holds the molecular determinants for transducin recognition: insights from computational analysis.

Oligomerization of a G protein-coupled receptor in neurons controlled by its structural dynamics

FEBS Letters — PNAS — Fluorescence resonance energy transfer studies of a human G protein-coupled receptor expressed in yeast. G protein-coupled receptor list. Pharmacological Reviews 57 — Annales de Physique 2 55 — Nature Current Opinion in Structural Biology 16 — Acta Physiologica 3 — 7.

Phylogenetic analysis, paralogon groups, and fingerprints. Molecular Pharmacology 63 — Endocrinology — Nature Methods 1 — EMBO Journal 20 — Journal of Neuroscience 24 — Neuropsychopharmacology 23 S60 — S Journal of Immunology — Molecular Pharmacology 69 45 — Hastings JW Chemistries and colors of bioluminescent reactions: a review. Gene 5 — Heroux M Hogue M Lemieux S Bouvier M Functional calcitonin gene-related peptide receptors are formed by the asymmetric assembly of a calcitonin receptor-like receptor homo-oligomer and a monomer of receptor activity-modifying protein Biochemistry 43 — Hu CD Kerppola TK Simultaneous visualization of multiple protein interactions in living cells using multicolor fluorescence complementation analysis.

Table of Contents

Nature Biotechnology 21 — Molecular Cell 9 — Molecular Endocrinology 20 — ChemMedChem 1 — Nature Methods 3 — Neurochemistry International 51 — Molecular Pharmacology 58 — Biochimica et Biophysica Acta 74 — Kerppola TK Design and implementation of bimolecular fluorescence complementation BiFC assays for the visualization of protein interactions in living cells. Nature Protocols 1 — Nature Methods 4 — Frontiers in Neuroendocrinology 24 — EMBO Journal 25 — Journal of Structural Biology — Lopez-Gimenez JF Canals M Pediani JD Milligan G The alpha1b-adrenoceptor exists as a higher-order oligomer: effective oligomerization is required for receptor maturation, surface delivery, and function.

Molecular Pharmacology 71 — Luttrell LM Transmembrane signaling by G protein-coupled receptors. Methods in Molecular Biology 3 — PNAS 90 — Maggio R Vogel Z Wess J b Reconstitution of functional muscarinic receptors by co-expression of amino- and carboxyl-terminal receptor fragments. Marullo S Bouvier M Resonance energy transfer approaches in molecular pharmacology and beyond. Trends in Pharmacological Sciences 28 — Analytical Biochemistry — The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy.

Milligan G G-protein-coupled receptor heterodimers: pharmacology, function and relevance to drug discovery. Drug Discovery Today 11 — Milligan G Bouvier M Methods to monitor the quaternary structure of G protein-coupled receptors. FEBS Journal — Life Sciences 74 — Minneman KP Heterodimerization and surface localization of G protein coupled receptors. Biochemical Pharmacology 73 — Reconstitution of the binding site by co-expression of two deficient mutants. Biochemical and Biophysical Research Communications — Cell — Journal of Endocrinology 17 — Current Biology 10 — Trends in Biochemical Sciences 31 — Journal of Neurochemistry 90 — PNAS 99 — Patel RC Lange DC Patel YC b Photobleaching fluorescence resonance energy transfer reveals ligand-induced oligomer formation of human somatostatin receptor subtypes.

Methods 27 — Pituitary 6 — Biochemical Journal — Cellular Signalling 18 — Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacological Reviews 59 5 — Brain Research Bulletin 70 — Ramsay D Kellett E McVey M Rees S Milligan G Homo- and hetero-oligomeric interactions between G-protein-coupled receptors in living cells monitored by two variants of bioluminescence resonance energy transfer BRET : hetero-oligomers between receptor subtypes form more efficiently than between less closely related sequences. Biophysical Journal 86 — Schertler GF Structure of rhodopsin and the metarhodopsin I photointermediate.

Current Opinion in Structural Biology 15 — Molecular Endocrinology 12 — Molecular Pharmacology 69 — Pharmacology and Therapeutics — Journal of Clinical Investigation 59 69 — Potential implications in receptor internalization. Tao YX Inactivating mutations of G protein-coupled receptors and diseases: structure—function insights and therapeutic implications. Characteristics of thyrotropin binding and solubilization of thyrotropin receptor activity by tryptic digestion.

Opioid Receptor Oligomerization

Vice versa, active receptor dimer configurations will likely require a conformationally flexible TM6 helix, i. Such a dimer-specific activity and functional selectivity could offer new opportunities to target GPCR function with medical drugs Hipser et al. Furthermore, an increasing number of studies suggests that dimerization and signaling of GPCRs are modulated by the surrounding membrane. This review will focus on how different types of lipids and other membrane components may influence dimerization patterns of GPCRs and thereby possibly regulate function and signaling.

There are two possible paths for how lipids may influence GPCRs association: by direct binding to the receptor surface, or indirectly by modulating the properties of the surrounding membrane. Here, we review and discuss available information for both mechanisms, as well as commonly employed methods for the study of GPCR oligomerization. Two frequently used methods to analyze GPCR dimer- or oligomerization are resonance energy transfer RET techniques and computational approaches such as molecular dynamics MD simulations.

The fluorescent proteins are usually variants of the green fluorescent protein GFP Shimomura et al. Due to the fact that the fluorophor proteins consist of approximately amino acids, hence are of comparable size as GPCRs themselves, the receptor stability needs to be tested and possible fluorophor-driven associations between the proteins should be excluded see e.


  • The Dry Eye: A Comprehensive Guide?
  • GPCR oligomer.
  • Class C G protein-coupled receptors: reviving old couples with new partners | SpringerLink;
  • GPCR oligomer.
  • Radiation Protection for Particle Accelerator Facilities: Recommendations of the National Council on Radiation Protection and Measurements (Ncrp Report).

As an alternative to the large GFP, small peptides binding extracellular fluorescein were presented that may in many cases reduce steric side effects Griffin et al. If the donor is excited via light waves at its absorbance wavelength and the acceptor is in close vicinity, FRET occurs between the donor and the acceptor resulting in a detectable emission of light from the acceptor see Figure 1. However, not only the distance but as well the relative orientations between donor and acceptor affect the energy transfer: If the dipoles are oriented perpendicular to each other, no FRET occurs.

Only a parallel orientation between donor and acceptor dipoles allows for a resonance energy transfer. Therefore, experimental instruments need to be justified carefully and extensive mathematical analysis of the collected signals is required for reliable conclusions. Additionally, the absence of FRET is not equivalent to the absence of protein-protein interactions, the fluorophors might not be in a close enough proximity or their relative dipole orientation might not be properly aligned, i.

G protein coupled receptor mediated signaling

Furthermore, the surrounding environment can quench the fluorescence up to a degree that no FRET signals can be detected. On the other hand, the overexpression of fluorescence proteins or high protein concentrations can lead to FRET between non-interacting proteins in close vicinity. Figure 1. In BRET assays, a bioluminescent protein e. The basic advantages of BRET techniques are the reduced background signal as compared to FRET methods, since the excitation is biochemically triggered instead of light-induced. Additionally, BRET enables to perform kinetical measurements, given that the signals can be detected for up to 30 min Cottet et al.

A notable drawback of BRET strategies as compared to FRET techniques is that the substrate not only excites the bioluminescent proteins at the cell surface but possibly as well cell-interior proteins. FRET and BRET techniques are very powerful tools to investigate protein association, however the interpretation of RET efficiencies can be rather challenging because different efficiencies can result from either an increased or decreased number of receptor oligomers or from conformational changes in preexisting complexes see Figure 1.

MD simulations provide atomistic detail of biomolecular processes at high spatial and time resolution and proved extremely useful in the study of GPCR dynamics, GPCR oligomer formation and in the analysis of the influence of the membrane environment on oligomerization Sabbadin et al. In general, MD simulations at atomistic resolution of biomolecular systems are limited to the timescale of hundreds of nanoseconds to a few microseconds.

However, protein aggregation occurs on timescales of tens of microseconds. Additionally, membrane systems typically contain more than , atoms and are therefore computationally rather expensive. A significant speedup is gained by switching to more coarse-grained resolutions.


  • Introduction.
  • LUND UNIVERSITY LIBRARIES!
  • Asterios Polyp.
  • GPCR oligomerization and receptor trafficking..
  • Turn To The Left And Kampf.
  • Class C G protein-coupled receptors: reviving old couples with new partners;
  • Chapter 6 - G Protein-Coupled Receptors (RSC Publishing).

For example, in the widely used Martini coarse-grained CG model, four heavy atoms are grouped together in one superatom or bead that reflects the properties of the 4 atoms Marrink et al. In this way, the number of degrees of freedom is reduced, high frequency motions of hydrogen atoms are excluded and the diffusion of proteins is increased by a reduced friction between CG beads as compared to atoms. Taken together, the computation time required to study a biomolecular process at CG resolution is by — times reduced as compared to a corresponding atomistic simulation.

Figure 2. Coarse-grained MD simulations.

Submit your work to JBC.

A Several molecules are shown as overlays between the atomistic and the corresponding Martini coarse-grained models. B A typical coarse-grained simulation system as used in receptor dimerization is shown before and after the simulation Pluhackova et al. Of course this loss of resolution comes with several drawbacks as compared to atomistic simulations. One important aspect in this regard is the inability of the CG force field to describe conformational changes of proteins, which is due to the simple design of the protein backbone in the Martini force field Marrink and Tieleman, In fact, the secondary structure is constrained by an additional force network to keep a preset structure de Jong et al.

Internalization Dissociates β2-Adrenergic Receptors

In addition, the reduction of resolution also affects the energy landscape of molecular systems: free solvation energies can be reproduced quite accurately in CG systems as compared to atomistic simulations, however, the decomposition of these free energies into enthalpic and entropic contributions can differ strongly Marrink and Tieleman, The reduction of the number of degrees of freedom influences the entropy of the system.

In order to reproduce the correct free energy, the enthalpic energies are therefore increased in the Martini model. In the same context, electrostatic interactions between charged particles are described implicitly in order to compensate the reduced number of partial charges and dipoles as compared to atomistic force fields. Consequently, Coulombic interactions in apolar environments are too weak in CG Martini models Marrink and Tieleman, Additionally, interactions between proteins in aqueous solution Stark et al. As a cure, it was shown for the older variant of the Martini force field that a reduction of the Lennard-Jones interactions between protein beads may compensate this overestimation Stark et al.

Nonetheless, the Martini forcefield shows good performance for membrane systems, hence it is commonly used to investigate transmembrane proteins on long timescales Pluhackova et al.