Detergent- and phospholipid-based reconstitution systems have differential effects on constitutive activity of G-protein-coupled receptors.

The Journal of Biological Chemistry
Dean P StausRobert J Lefkowitz

Abstract

A hallmark of G-protein-coupled receptors (GPCRs) is the conversion of external stimuli into specific cellular responses. In this tightly-regulated process, extracellular ligand binding by GPCRs promotes specific conformational changes within the seven transmembrane helices, leading to the coupling and activation of intracellular "transducer" proteins, such as heterotrimeric G proteins. Much of our understanding of the molecular mechanisms that govern GPCR activation is derived from experiments with purified receptors reconstituted in detergent micelles. To elucidate the influence of the phospholipid bilayer on GPCR activation, here we interrogated the functional, pharmacological, and biophysical properties of a GPCR, the β2-adrenergic receptor (β2AR), in high-density lipoprotein (HDL) particles. Compared with detergent-reconstituted β2AR, the β2AR in HDL particles had greatly enhanced levels of basal (constitutive) activity and displayed increased sensitivity to agonist activation, as assessed by activation of heterotrimeric G protein and allosteric coupling between the ligand-binding and transducer-binding pockets. Using 19F NMR spectroscopy, we directly linked these functional differences in detergent- and HDL-reconstituted ...Continue Reading

References

Oct 17, 2002·Naunyn-Schmiedeberg's Archives of Pharmacology·Roland Seifert, Katharina Wenzel-Seifert
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Xiao Jie YaoBrian Kobilka
Sep 8, 2010·Protein Engineering, Design & Selection : PEDS·Yelena V GrinkovaStephen G Sligar
Jan 14, 2011·Nature·Søren G F RasmussenBrian K Kobilka
Aug 16, 2012·The Journal of Biological Chemistry·Ka Young ChungR Scott Prosser
Feb 5, 2015·The Journal of Pharmacology and Experimental Therapeutics·Emma T van der WesthuizenArthur Christopoulos
Nov 17, 2015·Nature Chemical Biology·Rosie DawalibyCédric Govaerts
Nov 19, 2015·Proceedings of the National Academy of Sciences of the United States of America·Rajan LamichhaneDavid P Millar
Apr 5, 2017·Proceedings of the National Academy of Sciences of the United States of America·Ned Van EpsWayne L Hubbell
Jun 14, 2017·Nature·G Glenn GregorioScott C Blanchard
Oct 3, 2017·Biochemistry·Aashish Manglik, Andrew C Kruse
Mar 28, 2018·Proceedings of the National Academy of Sciences of the United States of America·Dean P StausRobert J Lefkowitz

❮ Previous
Next ❯

Citations

Apr 12, 2020·Angewandte Chemie·Evan S O'BrienA Joshua Wand
May 20, 2020·British Journal of Pharmacology·Kenneth A JacobsonJens Carlsson
Oct 21, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Andrew J Y JonesDaniel Nietlispach
Sep 27, 2020·The Journal of Biological Chemistry·Natalia PakharukovaRobert J Lefkowitz
Jan 18, 2021·The Journal of Biological Chemistry·Natalia PakharukovaRobert J Lefkowitz
Apr 20, 2021·The FEBS Journal·Daniel Hilger
Jun 16, 2021·Current Opinion in Structural Biology·Louis-Philippe Picard, Robert Scott Prosser
Feb 25, 2020·Biochemistry·Sho Hee Park, Jung Ho Lee
Sep 8, 2021·Frontiers in Molecular Biosciences·Evan van Aalst, Benjamin J Wylie
Nov 23, 2021·Journal of Chemical Information and Modeling·Jianfang ChenXuemei Pu

❮ Previous
Next ❯

Related Concepts

Related Feeds

ASBMB Publications

The American Society for Biochemistry and Molecular Biology (ASBMB) includes the Journal of Biological Chemistry, Molecular & Cellular Proteomics, and the Journal of Lipid Research. Discover the latest research from ASBMB here.

ApoE, Lipids & Cholesterol

Serum cholesterol, triglycerides, apolipoprotein B (APOB)-containing lipoproteins (very low-density lipoprotein (VLDL), immediate-density lipoprotein (IDL), and low-density lipoprotein (LDL), lipoprotein A (LPA)) and the total cholesterol/high-density lipoprotein (HDL) cholesterol ratio are all connected in diseases. Here is the latest research.

Adrenergic Receptors: Trafficking

Adrenergic receptor trafficking is an active physiological process where adrenergic receptors are relocated from one region of the cell to another or from one type of cell to another. Discover the latest research on adrenergic receptor trafficking here.

Related Papers

Tumour Biology : the Journal of the International Society for Oncodevelopmental Biology and Medicine
Kengo TakahashiTetsunari Oyama
Proceedings of the National Academy of Sciences of the United States of America
Seungkirl AhnRobert J Lefkowitz
© 2021 Meta ULC. All rights reserved