18
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      G Protein-Coupled Receptors (GPCRs) in Alzheimer’s Disease: A Focus on BACE1 Related GPCRs

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          The G protein coupled receptors (GPCRs) have been considered as one of the largest families of validated drug targets, which involve in almost overall physiological functions and pathological processes. Meanwhile, Alzheimer’s disease (AD), the most common type of dementia, affects thinking, learning, memory and behavior of elderly people, that has become the hotspot nowadays for its increasing risks and incurability. The above fields have been intensively studied, and the link between the two has been demonstrated, whereas the way how GPCRs perturb AD progress are yet to be further explored given their complexities. In this review, we summarized recent progress regarding the GPCRs interacted with β-site APP cleaving enzyme 1 (BACE1), a key secretase in AD pathogenesis. Then we discussed the current findings on the regulatory roles of GPCRs on BACE1, and the possibility for pharmaceutical treatment of AD patients by the allosteric modulators and biased ligands of GPCRs. We hope this review can provide new insights into the understanding of mechanistic link between GPCRs and BACE1, and highlight the potential of GPCRs as therapeutic target for AD.

          Related collections

          Most cited references142

          • Record: found
          • Abstract: found
          • Article: not found

          Crystal structure of rhodopsin: A G protein-coupled receptor.

          Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) respond to a variety of different external stimuli and activate G proteins. GPCRs share many structural features, including a bundle of seven transmembrane alpha helices connected by six loops of varying lengths. We determined the structure of rhodopsin from diffraction data extending to 2.8 angstroms resolution. The highly organized structure in the extracellular region, including a conserved disulfide bridge, forms a basis for the arrangement of the seven-helix transmembrane motif. The ground-state chromophore, 11-cis-retinal, holds the transmembrane region of the protein in the inactive conformation. Interactions of the chromophore with a cluster of key residues determine the wavelength of the maximum absorption. Changes in these interactions among rhodopsins facilitate color discrimination. Identification of a set of residues that mediate interactions between the transmembrane helices and the cytoplasmic surface, where G-protein activation occurs, also suggests a possible structural change upon photoactivation.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Structures of the CXCR4 chemokine GPCR with small-molecule and cyclic peptide antagonists.

            Chemokine receptors are critical regulators of cell migration in the context of immune surveillance, inflammation, and development. The G protein-coupled chemokine receptor CXCR4 is specifically implicated in cancer metastasis and HIV-1 infection. Here we report five independent crystal structures of CXCR4 bound to an antagonist small molecule IT1t and a cyclic peptide CVX15 at 2.5 to 3.2 angstrom resolution. All structures reveal a consistent homodimer with an interface including helices V and VI that may be involved in regulating signaling. The location and shape of the ligand-binding sites differ from other G protein-coupled receptors and are closer to the extracellular surface. These structures provide new clues about the interactions between CXCR4 and its natural ligand CXCL12, and with the HIV-1 glycoprotein gp120.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Crystal structure of the μ-opioid receptor bound to a morphinan antagonist

              Summary Opium is one of the world’s oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many of their undesirable side effects (sedation, apnea and dependence) by binding to and activating the G-protein-coupled μ-opioid receptor (μOR) in the central nervous system. Here we describe the 2.8 Å crystal structure of the μOR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most GPCRs published to date, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the μOR crystallizes as a two-fold symmetric dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.
                Bookmark

                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                24 March 2016
                2016
                : 8
                : 58
                Affiliations
                [1] 1School of Life Science, Beijing Institute of Technology Beijing, China
                [2] 2School of Physics, Beijing Institute of Technology Beijing, China
                Author notes

                Edited by: George E. Barreto, Pontificia Universidad Javeriana, Colombia

                Reviewed by: Valentina Echeverria Moran, Bay Pines VA Medical Center, USA; Francisco G. Wandosell, Universidad Autónoma de Madrid, Spain

                *Correspondence: Hong Qing hqing@ 123456bit.edu.cn
                Article
                10.3389/fnagi.2016.00058
                4805599
                27047374
                d83985e0-65e0-4edc-9b69-61f5b68ef025
                Copyright © 2016 Zhao, Deng, Jiang and Qing.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution and reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 January 2016
                : 08 March 2016
                Page count
                Figures: 4, Tables: 2, Equations: 0, References: 168, Pages: 15, Words: 13251
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 8157051211
                Categories
                Neuroscience
                Review

                Neurosciences
                g protein-coupled protein (gpcr),alzheimer’s disease (ad),β-site app cleaving enzyme 1 (bace1),allosteric modulator,biased ligand

                Comments

                Comment on this article