Effector membrane translocation biosensors reveal G protein and βarrestin coupling profiles of 100 therapeutically relevant GPCRs

被引：144

作者：

Avet, Charlotte ^{[1
,2
]}

Mancini, Arturo ^{[3
]}

Breton, Billy ^{[1
,3
]}

Le Gouill, Christian ^{[1
,2
]}

Hauser, Alexander S. ^{[4
]}

Normand, Claire ^{[3
]}

Kobayashi, Hiroyuki ^{[1
,2
]}

Gross, Florence ^{[3
]}

Hogue, Mireille ^{[1
,2
]}

Lukasheva, Viktoriya ^{[1
,2
]}

St-Onge, Stephane ^{[1
,2
]}

Carrier, Marilyn ^{[1
,2
]}

Heroux, Madeleine ^{[1
,2
]}

Morissette, Sandra ^{[3
]}

Fauman, Eric B. ^{[5
]}

Fortin, Jean-Philippe ^{[6
]}

Schann, Stephan ^{[7
]}

Leroy, Xavier ^{[7
]}

Gloriam, David E. ^{[4
]}

Bouvier, Michel ^{[1
,2
]}

机构：

[1] Univ Montreal, IRIC, Montreal, PQ, Canada

[2] Univ Montreal, Dept Biochem & Mol Med, Montreal, PQ, Canada

[3] Domain Therapeut North Amer, Montreal, PQ, Canada

[4] Univ Copenhagen, Dept Drug Design & Pharmacol, Copenhagen, Denmark

[5] Pfizer Worldwide Res, Dev & Med, Internal Med Res Unit, Cambridge, MA USA

[6] Pfizer Global R&D, Cambridge, MA USA

[7] Domain Therapeut, Illkirch Graffenstaden, France

来源：

ELIFE | 2022年 / 11卷

关键词：

ACTIVATION; RECEPTOR; G-ALPHA(Q); P63RHOGEF; RAP1GAP; TARGETS; CELLS; FORM;

D O I：

10.7554/eLife.74101

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

The recognition that individual GPCRs can activate multiple signaling pathways has raised the possibility of developing drugs selectively targeting therapeutically relevant ones. This requires tools to determine which G proteins and beta arrestins are activated by a given receptor. Here, we present a set of BRET sensors monitoring the activation of the 12 G protein subtypes based on the translocation of their effectors to the plasma membrane (EMTA). Unlike most of the existing detection systems, EMTA does not require modification of receptors or G proteins (except for G(s)). EMTA was found to be suitable for the detection of constitutive activity, inverse agonism, biased signaling and polypharmacology. Profiling of 100 therapeutically relevant human GPCRs resulted in 1500 pathway-specific concentration-response curves and revealed a great diversity of coupling profiles ranging from exquisite selectivity to broad promiscuity. Overall, this work describes unique resources for studying the complexities underlying GPCR signaling and pharmacology.

引用

页数：34

共 59 条

[1] Plasma Membrane Association of p63 Rho Guanine Nucleotide Exchange Factor (p63RhoGEF) Is Mediated by Palmitoylation and Is Required for Basal Activity in Cells [J].

Aittaleb, Mohamed ;

Nishimura, Akiyuki ;

Linder, Maurine E. ;

Tesmer, John J. G. .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2011, 286 (39) :34448-34456

[2] Structure and Function of Heterotrimeric G Protein-Regulated Rho Guanine Nucleotide Exchange Factors [J].

Aittaleb, Mohamed ;

Boguth, Cassandra A. ;

Tesmer, John J. G. .

MOLECULAR PHARMACOLOGY, 2010, 77 (02) :111-125

[3] The chemokine CXC4 and CC2 receptors form homo- and heterooligomers that can engage their signaling G-protein effectors and βarrestin [J].

Armando, Sylvain ;

Quoyer, Julie ;

Lukashova, Viktorya ;

Maiga, Arhamatoulaye ;

Percherancier, Yann ;

Heveker, Nikolaus ;

Pin, Jean-Philippe ;

Prezeau, Laurent ;

Bouvier, Michel .

FASEB JOURNAL, 2014, 28 (10) :4509-4523

[4] Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis [J].

Atwood B.K. ;

Lopez J. ;

Wager-Miller J. ;

Mackie K. ;

Straiker A. .

BMC Genomics, 12 (1)

[5] The PAR2 inhibitor I-287 selectively targets Gαq and Gα12/13 signaling and has anti-inflammatory effects [J].

Avet, Charlotte ;

Sturino, Claudio ;

Grastilleur, Sebastien ;

Le Gouill, Christian ;

Semache, Meriem ;

Gross, Florence ;

Gendron, Louis ;

Bennani, Youssef ;

Mancini, Joseph A. ;

Sayegh, Camil E. ;

Bouvier, Michel .

COMMUNICATIONS BIOLOGY, 2020, 3 (01)

[6] β-Arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors [J].

Azzi, M ;

Charest, PG ;

Angers, S ;

Rousseau, G ;

Kohout, T ;

Bouvier, M ;

Piñeyro, G .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (20) :11406-11411

[7] Reducing safety-related drug attrition: the use of in vitro pharmacological profiling [J].

Bowes, Joanne ;

Brown, Andrew J. ;

Hamon, Jacques ;

Jarolimek, Wolfgang ;

Sridhar, Arun ;

Waldron, Gareth ;

Whitebread, Steven .

NATURE REVIEWS DRUG DISCOVERY, 2012, 11 (12) :909-922

[8] Comparative effect of L-CCG-I, DCG-IV and γ-carboxy-L-glutamate on all cloned metabotropic glutamate receptor subtypes [J].

Brabet, I ;

Parmentier, ML ;

De Colle, C ;

Bockaert, J ;

Acher, F ;

Pin, JP .

NEUROPHARMACOLOGY, 1998, 37 (08) :1043-1051

[9] Multiplexing of Multicolor Bioluminescence Resonance Energy Transfer [J].

Breton, Billy ;

Sauvageau, Etienne ;

Zhou, Joris ;

Bonin, Helene ;

Le Gouill, Christian ;

Bouvier, Michel .

BIOPHYSICAL JOURNAL, 2010, 99 (12) :4037-4046

[10] Gi protein activation in intact cells involves subunit rearrangement rather than dissociation [J].

Bünemann, M ;

Frank, M ;

Lohse, MJ .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2003, 100 (26) :16077-16082

← 1 2 3 4 5 6 →