Identification of Key Regions Mediating Human Melatonin Type 1 Receptor Functional Selectivity Revealed by Natural Variants

2021 ◽  
Author(s):  
Alan Hegron ◽  
Eunna Huh ◽  
Xavier Deupi ◽  
Badr Sokrat ◽  
Wenwen Gao ◽  
...  
Keyword(s):  
Functional Selectivity ◽  
Natural Variants

Pharmacologic Perspectives of Functional Selectivity by the Angiotensin II Type 1 Receptor

2008 ◽  
Vol 18 (8) ◽  
pp. 305-312 ◽  
Author(s):  
Mark Aplin ◽  
Gitte Lund Christensen ◽  
Jakob Lerche Hansen
Keyword(s):  
Angiotensin Ii ◽  
Functional Selectivity

scholarly journals Analysis of Natural Variants of the Human Immunodeficiency Virus Type 1 gag-pol Frameshift Stem-Loop Structure

2002 ◽  
Vol 76 (15) ◽  
pp. 7868-7873 ◽  
Author(s):  
Amalio Telenti ◽  
Raquel Martinez ◽  
Miguel Munoz ◽  
Gabriela Bleiber ◽  
Gilbert Greub ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Viral Replication ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Thermodynamic Stability ◽  
Stem Loop ◽  
Stem Loop Structure ◽  
Immunodeficiency Virus ◽  
Natural Variants

ABSTRACT Human immunodeficiency virus type 1 uses ribosomal frameshifting for translation of the Gag-Pol polyprotein. Frameshift activities are thought to be tightly regulated. Analysis of gag p1 sequences from 270 plasma virions identified in 64% of the samples the occurrence of polymorphism that could lead to changes in thermodynamic stability of the stem-loop. Expression in Saccharomyces cerevisiae of p1-β-galactosidase fusion proteins from 10 representative natural stem-loop variants and three laboratory mutant constructs (predicted the thermodynamic stability [ΔG°] ranging from −23.0 to −4.3 kcal/mol) identified a reduction in frameshift activity of 13 to 67% compared with constructs with the wild-type stem-loop (ΔG°, −23.5 kcal/mol). Viruses carrying stem-loops associated with greater than 60% reductions in frameshift activity presented profound defects in viral replication. In contrast, viruses with stem-loop structures associated with 16 to 42% reductions in frameshift efficiency displayed no significant viral replication deficit.

scholarly journals Type 1 Cannabinoid Receptor Ligands Display Functional Selectivity in a Cell Culture Model of Striatal Medium Spiny Projection Neurons

2014 ◽  
Vol 289 (36) ◽  
pp. 24845-24862 ◽  
Author(s):  
Robert B. Laprairie ◽  
Amina M. Bagher ◽  
Melanie E. M. Kelly ◽  
Denis J. Dupré ◽  
Eileen M. Denovan-Wright
Keyword(s):  
Cell Culture ◽  
Cannabinoid Receptor ◽  
Projection Neurons ◽  
Functional Selectivity ◽  
Receptor Ligands ◽  
Cell Culture Model ◽  
Culture Model ◽  
A Cell ◽  
Type 1 Cannabinoid Receptor

Natural variants of the sabin type 1 vaccine strain of poliovirus and correlation with a poliovirus neutralization site

Virology ◽  
1985 ◽  
Vol 143 (1) ◽  
pp. 337-341 ◽  
Author(s):  
Bradford A. Jameson ◽  
Jutta Bonin ◽  
Eckard Wimmer ◽  
Olen M. Kew
Keyword(s):  
Vaccine Strain ◽  
Natural Variants

scholarly journals Identification of key regions mediating human melatonin type 1 receptor biased signaling revealed by natural variants

2018 ◽  
Vol 32 (S1) ◽  
Author(s):  
Alan HEGRON ◽  
Bianca PLOUFFE ◽  
Amelie BONNEFOND ◽  
Wenwen GAO ◽  
Philippe FROGUEL ◽  
...  
Keyword(s):  
Biased Signaling ◽  
Natural Variants

Functional selectivity profiling of the angiotensin II type 1 receptor using pathway-wide BRET signaling sensors

2018 ◽  
Vol 11 (559) ◽  
pp. eaat1631 ◽  
Author(s):  
Yoon Namkung ◽  
Christian LeGouill ◽  
Sahil Kumar ◽  
Yubo Cao ◽  
Larissa B. Teixeira ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
G Proteins ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Functional Selectivity ◽  
Gpcr Signaling ◽  
Downstream Signaling ◽  
Protein Levels

G protein–coupled receptors (GPCRs) are important therapeutic targets that exhibit functional selectivity (biased signaling), in which different ligands or receptor variants elicit distinct downstream signaling. Understanding all the signaling events and biases that contribute to both the beneficial and adverse effects of GPCR stimulation by given ligands is important for drug discovery. Here, we report the design, validation, and use of pathway-selective bioluminescence resonance energy transfer (BRET) biosensors that monitor the engagement and activation of signaling effectors downstream of G proteins, including protein kinase C (PKC), phospholipase C (PLC), p63RhoGEF, and Rho. Combined with G protein and β-arrestin BRET biosensors, our sensors enabled real-time monitoring of GPCR signaling at different levels in downstream pathways in both native and engineered cells. Profiling of the responses to 14 angiotensin II (AngII) type 1 receptor (AT1R) ligands enabled the clustering of compounds into different subfamilies of biased ligands and showed that, in addition to the previously reported functional selectivity between Gαq and β-arrestin, there are also biases among G protein subtypes. We also demonstrated that biases observed at the receptor and G protein levels propagated to downstream signaling pathways and that these biases could occur through the engagement of different G proteins to activate a common effector. We also used these tools to determine how naturally occurring AT1R variants affected signaling bias. This suite of BRET biosensors provides a useful resource for fingerprinting biased ligands and mutant receptors and for dissecting functional selectivity at various levels of GPCR signaling.

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