Heterotrimeric G Protein Subunit Gαq is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs

Pfeil, Eva Marie; Vescovo, Maddalena; Vögtle, Timo; Brands, Julian; Rick, Ulrike; Merten, Nicole; Albrecht, Ina-Maria; Kawakami, Koki; Ono, Yukiko; Kadji, Francois Marie Ngako; Aoki, Junken; Häberlein, Felix; Matthey, Michaela; Garg, Jaspal; Hennen, Stephanie; Jobin, Marie‐Lise; Seier, Kerstin; Calebiro, Davide; Pfeifer, Alexander; Heinemann, Ákos; Wenzel, Daniela; König, Gabriele M.; Nieswandt, Bernhard; Fleischmann, Bernd K.; Inoue, Asuka; Simon, Katharina; Kostenis, Evi

doi:10.2139/ssrn.3578140

Cited by 12 publications

(19 citation statements)

References 97 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As GPR17-stimulated calcium mobilization is mediated by both Gq and Gi/o-Gβγ subunits (29), we investigated the contributions of Gi/o-Gβγ subunits to hGPR17L-V96M and -D105N variant-mediated calcium mobilization by using pertussis toxin to inhibit Gi/o-Gβγ subunits (Figure S6). Consistent with a previous report (29), pertussis toxin treatment had modest effects on MDL29,951-stimulated hGPR17L-WT calcium flux, with reduced efficacy (82±1.4% of control pretreatment) and potency (approximately 2.5-fold shift in EC 50 ). Furthermore, reduced calcium mobilization was also observed for hGPR17L-V96M and hGPR17L-D105N in the presence of pertussis toxin, suggesting that Gi/o-Gβγ subunits contribute to calcium responses for these hGPR17L variants.…”

Section: Human Gpr17 Variants Had Distinct Calcium Signaling Activitiessupporting

confidence: 91%

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

Conley

Sun

Ayers

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

show abstract

Section: Human Gpr17 Variants Had Distinct Calcium Signaling Activitiessupporting

confidence: 91%

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

Conley

Sun

Ayers

et al. 2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Intracellular signaling was assessed in human primary astrocytes. S1P 1 is reported to only couple with Gα i protein but transduces signals to not only cyclic AMP, but also Ca 2+ , possibly through a coupling of released Gβγ with proximal Gα q protein 25 . S1P induced Ca 2+ signals in a concentration‐dependent manner (logEC 50 = −7.031 ± 0.063, n = 4; Figure 2A and Table S1).…”

Section: Resultsmentioning

confidence: 97%

“…Direct receptor binding as determined here by CIR showed somewhat lower affinities than those published for other agents and identified here for siponimod. 41 Ponesimod showed inhibition of both S1P-induced intracellular Ca 2+ via Gαi-Gβγ-Gαqmediated signaling 25 and Gαi-mediated cAMP responses, at least within human primary astrocytes. On the other hand, functional antagonism by fingolimod appeared to be biased for the βarrestin pathway because fingolimod-P induced sustained S1P 1 internalization but did not block intracellular signals.…”

Section: Discussionmentioning

confidence: 96%

“…S1P 1 is reported to only couple with Gα i protein but transduces signals to not only cyclic AMP, but also Ca 2+ , possibly through a coupling of released Gβγ with proximal Gα q protein. 25 S1P induced Ca 2+ signals in a concentration-dependent manner (logEC 50 = −7.031 ± 0.063, n = 4; Figure 2A and Table S1). However, none of the S1PR modulators (ponesimod, siponimod, ozanimod, or fingolimod-P) affected intracellular Ca 2+ mobilization under our assay conditions (Figure 2A and Table S1; ponesimod induced a Ca 2+ signal only at the highest concentration (30 µM), Figure S1).…”

Section: Ponesimod Inhibits S1p-induced Intracellular Signals In Human Primary Astrocytesmentioning

confidence: 99%

See 1 more Smart Citation

Ponesimod inhibits astrocyte‐mediated neuroinflammation and protects against cingulum demyelination via S1P ₁ ‐selective modulation

et al. 2022

View full text Add to dashboard Cite

Ponesimod is a sphingosine 1‐phosphate (S1P) receptor (S1PR) modulator that was recently approved for treating relapsing forms of multiple sclerosis (MS). Three other FDA‐approved S1PR modulators for MS—fingolimod, siponimod, and ozanimod—share peripheral immunological effects via common S1P1 interactions, yet ponesimod may access distinct central nervous system (CNS) mechanisms through its selectivity for the S1P1 receptor. Here, ponesimod was examined for S1PR internalization and binding, human astrocyte signaling and single‐cell RNA‐seq (scRNA‐seq) gene expression, and in vivo using murine cuprizone‐mediated demyelination. Studies confirmed ponesimod’s selectivity for S1P1 without comparable engagement to the other S1PR subtypes (S1P2,3,4,5). Ponesimod showed pharmacological properties of acute agonism followed by chronic functional antagonism of S1P1. A major locus of S1P1 expression in the CNS is on astrocytes, and scRNA‐seq of primary human astrocytes exposed to ponesimod identified a gene ontology relationship of reduced neuroinflammation and reduction in known astrocyte disease‐related genes including those of immediate early astrocytes that have been strongly associated with disease progression in MS animal models. Remarkably, ponesimod prevented cuprizone‐induced demyelination selectively in the cingulum, but not in the corpus callosum. These data support the CNS activities of ponesimod through S1P1, including protective, and likely selective, effects against demyelination in a major connection pathway of the brain, the limbic fibers of the cingulum, lesions of which have been associated with several neurologic impairments including MS fatigue.

show abstract

“…sensitive to the Gi inhibitor pertussis toxin). Thus, the concept of potential scaffolding of PLC by Gq may be required for Gi-derived Gbg activation (10).…”

Section: Gs or Gi/o Coupling Is Selective While G12/13 Is Promiscuous...mentioning

confidence: 99%

Common coupling map advances GPCR-G protein selectivity

Hauser

Avet

Normand³

et al. 2021

Preprint

Self Cite

View full text Add to dashboard Cite

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 meta-analysis unifying GPCR-G protein coupling, by standardized normalization and consensus support, into a common coupling map. This unravels novel consensus couplings for receptors supported by two independent sources and insights on coupling selectivity of GPCRs and classification of co-coupling G proteins. The coupling protocol, map and selectivity resources will promote advances in receptor research and cellular signaling towards the exploitation of G protein signaling specificity in design of safer drugs.

show abstract

Heterotrimeric G Protein Subunit Gαq is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs

Cited by 12 publications

References 97 publications

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

Ponesimod inhibits astrocyte‐mediated neuroinflammation and protects against cingulum demyelination via S1P ₁ ‐selective modulation

Common coupling map advances GPCR-G protein selectivity

Contact Info

Product

Resources

About

Heterotrimeric G Protein Subunit Gαq is a Master Switch for Gβγ-Mediated Calcium Mobilization by Gi-Coupled GPCRs

Cited by 12 publications

References 97 publications

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

Human GPR17 missense variants identified in metabolic disease patients have distinct downstream signaling profiles

Ponesimod inhibits astrocyte‐mediated neuroinflammation and protects against cingulum demyelination via S1P 1 ‐selective modulation

Common coupling map advances GPCR-G protein selectivity

Contact Info

Product

Resources

About

Ponesimod inhibits astrocyte‐mediated neuroinflammation and protects against cingulum demyelination via S1P ₁ ‐selective modulation