Next Article in Journal
Comparative Proteomic Analysis of Lysine Acetylation in Fish CIK Cells Infected with Aquareovirus
Next Article in Special Issue
RNA Chaperone Function of a Universal Stress Protein in Arabidopsis Confers Enhanced Cold Stress Tolerance in Plants
Previous Article in Journal
A Role of Sp1 Binding Motifs in Basal and Large T-Antigen-Induced Promoter Activities of Human Polyomavirus HPyV9 and Its Variant UF-1
Previous Article in Special Issue
Hsp90α Mediates BMI1 Expression in Breast Cancer Stem/Progenitor Cells through Facilitating Nuclear Translocation of c-Myc and EZH2
Article Menu
Issue 11 (November) cover image

Export Article

Open AccessReview
Int. J. Mol. Sci. 2017, 18(11), 2416; https://doi.org/10.3390/ijms18112416

Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding-Deficient Mutant GPCRs and SLC6 Transporters

Institute of Pharmacology and the Gaston H. Glock Research Laboratories for Exploratory Drug Development, Center of Physiology and Pharmacology, Medical University of Vienna, A-1090 Vienna, Austria
*
Author to whom correspondence should be addressed.
Received: 28 October 2017 / Revised: 11 November 2017 / Accepted: 12 November 2017 / Published: 14 November 2017
(This article belongs to the Special Issue Molecular Chaperones)
View Full-Text   |   Download PDF [1221 KB, uploaded 14 November 2017]   |  

Abstract

Many diseases arise from mutations, which impair protein folding. The study of folding-deficient variants of G protein-coupled receptors and solute carrier 6 (SLC6) transporters has shed light on the folding trajectory, how it is monitored and how misfolding can be remedied. Reducing the temperature lowers the energy barrier between folding intermediates and thereby eliminates stalling along the folding trajectory. For obvious reasons, cooling down is not a therapeutic option. One approach to rescue misfolded variants is to use membrane-permeable orthosteric ligands. Antagonists of GPCRs are—in many instances—effective pharmacochaperones: they restore cell surface expression provided that they enter cells and bind to folding intermediates. Pharmacochaperoning of SLC6 transporters is less readily achieved because the ionic conditions in the endoplasmic reticulum (ER) are not conducive to binding of typical inhibitors. The second approach is to target the heat-shock protein (HSP) relay, which monitors the folding trajectory on the cytosolic side. Importantly, orthosteric ligands and HSP-inhibitors are not mutually exclusive. In fact, pharmacochaperones and HSP-inhibitors can act in an additive or synergistic manner. This was exemplified by rescuing disease-causing, folding-deficient variants of the human dopamine transporters with the HSP70 inhibitor pifithrin-μ and the pharmacochaperone noribogaine in Drosophila melanogaster. View Full-Text
Keywords: G protein coupled receptors/GPCRs; solute carrier 6/SLC6; misfolding; heat-shock protein relay; pharmacochaperoning; heat-shock protein inhibitors G protein coupled receptors/GPCRs; solute carrier 6/SLC6; misfolding; heat-shock protein relay; pharmacochaperoning; heat-shock protein inhibitors
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Share & Cite This Article

MDPI and ACS Style

Asjad, H.M.; Nasrollahi-Shirazi, S.; Sucic, S.; Freissmuth, M.; Nanoff, C. Relax, Cool Down and Scaffold: How to Restore Surface Expression of Folding-Deficient Mutant GPCRs and SLC6 Transporters. Int. J. Mol. Sci. 2017, 18, 2416.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Int. J. Mol. Sci. EISSN 1422-0067 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top