An inactive receptor-G protein complex maintains the dynamic range of agonist-induced signaling.

Proceedings of the National Academy of Sciences of the United States of America
Wonjo JangNevin A Lambert

Abstract

Agonist binding promotes activation of G protein-coupled receptors (GPCRs) and association of active receptors with G protein heterotrimers. The resulting active-state ternary complex is the basis for conventional stimulus-response coupling. Although GPCRs can also associate with G proteins before agonist binding, the impact of such preassociated complexes on agonist-induced signaling is poorly understood. Here we show that preassociation of 5-HT7 serotonin receptors with Gs heterotrimers is necessary for agonist-induced signaling. 5-HT7 receptors in their inactive state associate with Gs, as these complexes are stabilized by inverse agonists and receptor mutations that favor the inactive state. Inactive-state 5-HT7-Gs complexes dissociate in response to agonists, allowing the formation of conventional agonist-5-HT7-Gs ternary complexes and subsequent Gs activation. Inactive-state 5-HT7-Gs complexes are required for the full dynamic range of agonist-induced signaling, as 5-HT7 receptors spontaneously activate Gs variants that cannot form inactive-state complexes. Therefore, agonist-induced signaling in this system involves two distinct receptor-G protein complexes, a conventional ternary complex that activates G proteins and an...Continue Reading

References

Apr 1, 1997·Trends in Pharmacological Sciences·R M EglenG R Martin
Aug 29, 1997·The Journal of Biological Chemistry·R K SunaharaA G Gilman
Aug 27, 1999·Trends in Pharmacological Sciences·R SeifertB K Kobilka
May 12, 2000·British Journal of Pharmacology·D R ThomasG W Price
Sep 5, 2002·Nature Reviews. Molecular Cell Biology·Kristen L PierceRobert J Lefkowitz
Jun 27, 2003·Cellular and Molecular Neurobiology·Paul A Insel, Rennolds S Ostrom
Mar 23, 2005·Nature Methods·Céline GalésMichel Bouvier
Mar 5, 2009·Cellular Signalling·Bettye HollinsNevin A Lambert
May 28, 2009·Proceedings of the National Academy of Sciences of the United States of America·Xiao Jie YaoBrian Kobilka
Feb 7, 2014·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Michaela B C KilanderGunnar Schulte
Jan 22, 2015·Proceedings of the National Academy of Sciences of the United States of America·Marjorie DamianJean-Louis Banères
Apr 22, 2015·Nature Structural & Molecular Biology·Wesley K KroezeBryan L Roth
Apr 21, 2017·PloS One·Rony NehméChristopher G Tate
Oct 6, 2017·Biophysical Journal·Michael L BlinovLeslie M Loew
Oct 29, 2017·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Kjetil Wessel AndressenFinn Olav Levy
Mar 11, 2018·The Journal of Biological Chemistry·Qingwen WanNevin A Lambert
Jun 22, 2018·Annual Review of Biochemistry·William I Weis, Brian K Kobilka
Dec 7, 2018·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Andrea Hembre UlsundK W Andressen
May 14, 2019·Cell·Yang DuKa Young Chung
May 31, 2019·Proceedings of the National Academy of Sciences of the United States of America·Najeah OkashahNevin A Lambert
Jun 5, 2019·Cell·Asuka InoueRobert B Russell
Dec 20, 2019·ELife·Qingtong ZhouSuwen Zhao
Mar 4, 2020·Nature Communications·Tao CheBryan L Roth

❮ Previous
Next ❯

Citations

Dec 8, 2020·The FEBS Journal·Alexey Bondar, Josef Lazar
May 29, 2021·Current Opinion in Structural Biology·Shane C Wright, Michel Bouvier

❮ Previous
Next ❯

Methods Mentioned

BETA
BRET
pull-down
PCR
Transfection

Software Mentioned

VCell
Virtual Cell ( VCell )

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.