Common coupling map advances GPCR-G protein selectivity

Abstract

Two-thirds of human hormones and one-third of clinical drugs act on membrane receptors that couple to G proteins to achieve appropriate functional responses. While G protein transducers from literature are annotated in the Guide to Pharmacology database, two recent large-scale datasets now expand the receptor-G protein 'couplome'. However, these three datasets differ in scope and reported G protein couplings giving different coverage and conclusions on GPCR-G protein signaling. Here, we report a common coupling map uncovering novel couplings supported by both large-scale studies, the selectivity/promiscuity of GPCRs and G proteins, and how the co-coupling and co-expression of G proteins compare to the families from phylogenetic relationships. The coupling map and insights on GPCR-G protein selectivity will catalyze advances in receptor research and cellular signaling towards the exploitation of G protein signaling bias in design of safer drugs.

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

“…Indeed, 27% of the receptors coupling to G i/o only activated this subtype family in comparison to 0, 2.4 and 9.1% for receptors activating G 12/13 , G q/11 , and G s , respectively, thus displaying more promiscuous coupling. A detailed comparative analysis of the selectivity profiles that we observed using the EMTA sensors with that of the chimeric G protein-based assay developed by Inoue et al, 2019 and the IUPHAR/BPS Guide to Pharmacology database (GtP; https://www.guidetopharmacology.org/ ) is presented in the accompanying paper ( Hauser et al, 2022 ). Supplementary file 2C allows a direct comparison of the relative potency determined using EMTA for both the new and the already known (i.e.…”

“…Of note, this comparison only considers the final reported couplings that in the Inoue’s study were based on the criteria of positive coupling if LogRAi ≥ –1 and negative coupling if LogRAi ≤ –1, and is influenced by the different cut-offs and normalization used in the two studies. A comparison of couplings using common E max standard deviation cut-off, quantitative normalization and aggregation of G proteins into families is provided in the accompanying paper ( Hauser et al, 2022 ). As can be seen in Supplementary file 4A , among the 70 receptors common to both studies, less couplings were detected in our study than reported in Inoue et al for Gα s (21 vs. 28), Gα i1 (54 vs. 56), Gα q (31 vs. 34), and Gα 14 (36 vs. 40).…”

“…#: H-5645 Chemical compound, drug Ghrelin Tocris Cat. #: 1,463 Chemical compound, drug Glucagon ( Aittaleb et al, 2010 ; Aittaleb et al, 2011 ; Armando et al, 2014 ; Atwood et al, 2011 ; Avet et al, 2020 ; Azzi et al, 2003 ; Bowes et al, 2012 ; Brabet et al, 1998 ; Breton et al, 2010 ; Bünemann et al, 2003 ; Carr et al, 2014 ; Casey et al, 1990 ; Chandan et al, 2021 ; De Haan and Hirst, 2004 ; Devost et al, 2017 ; Fukuhara et al, 2001 ; Galandrin et al, 2007 ; Galés et al, 2005 ; Galés et al, 2006 ; Goupil et al, 2015 ; Hauser et al, 2017 ; Hauser et al, 2022 ; Hoffmann et al, 2005 ; Inoue et al, 2019 ; Jordan et al, 1999 ; Kawamata et al, 2003 ; Kenakin, 2019 ; Kim et al, 2002 ) Bachem Cat. #: H-6790 Chemical compound, drug Glucagon-like peptide-1 GLP-1 ( Bowes et al, 2012 ; Brabet et al, 1998 ; Breton et al, 2010 ; Bünemann et al, 2003 ; Carr et al, 2014 ; Casey et al, 1990 ; Chandan et al, 2021 ; De Haan and Hirst, 2004 ; …”

“…#: H-6790 Chemical compound, drug Glucagon-like peptide-1 GLP-1 ( Bowes et al, 2012 ; Brabet et al, 1998 ; Breton et al, 2010 ; Bünemann et al, 2003 ; Carr et al, 2014 ; Casey et al, 1990 ; Chandan et al, 2021 ; De Haan and Hirst, 2004 ; Devost et al, 2017 ; Fukuhara et al, 2001 ; Galandrin et al, 2007 ; Galés et al, 2005 ; Galés et al, 2006 ; Goupil et al, 2015 ; Hauser et al, 2017 ; Hauser et al, 2022 ; Hoffmann et al, 2005 ; Inoue et al, 2019 ; Jordan et al, 1999 ; Kawamata et al, 2003 ; Kenakin, 2019 ; Kim et al, 2002 ; Kobayashi et al, 2019 ; Laschet et al, 2019 ; Lavoie et al, 2002 ; Leduc et al, 2009 ; Leguay et al, 2021 ; Lu et al, 2014 ; Lutz et al, 2007 ) Bachem Cat. #: H-6795 Chemical compound, drug Glucagon-like peptide-2 GLP-2 ( Aittaleb et al, 2010 ; Aittaleb et al, 2011 ; Armando et al, 2014 ; Atwood et al, 2011 ; Avet et al, 2020 ; Azzi et al, 2003 ; Bowes et al, 2012 ; Brabet et al, 1998 ; Breton et al, 2010 ; Bünemann et al, 2003 ; Carr et al, 2014 ; Casey et al, 1990 …”

The Location of Missense Variants in the Human GIP Gene Is Indicative for Natural Selection

“…We focused on the 41 genetic variants found in GIP(1-42) to dissect different peptide regions as they exhibit differential features with respect to receptor interaction. Taking the twodomain binding mechanism into account (35), GIP(1-42) was divided into three segments: a N-terminal segment (residue 1-15), a core segment (residue 16-30), and a C-terminal segment (residue [31][32][33][34][35][36][37][38][39][40][41][42].…”