Muscarinic allosteric modulation: M 2 /M 3 subtype selectivity of gallamine is independent of G-protein coupling specificity

2001 ◽  
Vol 364 (2) ◽  
pp. 172-178 ◽  
Author(s):  
Christian Tränkle ◽  
Evi Kostenis ◽  
Klaus Mohr
Keyword(s):  
G Protein ◽  
Allosteric Modulation ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Subtype Selectivity ◽  
Coupling Specificity

scholarly journals The allosteric enhancer PD81,723 increases chimaeric A1/A2A adenosine receptor coupling with Gs

2006 ◽  
Vol 396 (1) ◽  
pp. 139-146 ◽  
Author(s):  
Samita Bhattacharya ◽  
Rebecca L. Youkey ◽  
Kobina Ghartey ◽  
Matthew Leonard ◽  
Joel Linden ◽  
...  
Keyword(s):  
G Protein ◽  
Adenosine Receptor ◽  
Intracellular Loop ◽  
Dissociation Kinetics ◽  
A2a Adenosine Receptor ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Receptor Coupling ◽  
A1 Receptor ◽  
Coupling Specificity

PD81,723 {(2-amino-4,5-dimethyl-3-thienyl)-[3-(trifluromethyl)-phenyl]methanone} is a selective allosteric enhancer of the Gi-coupled A1 AR (adenosine receptor) that is without effect on Gs-coupled A2A ARs. PD81,723 elicits a decrease in the dissociation kinetics of A1 AR agonist radioligands and an increase in functional agonist potency. In the present study, we sought to determine whether enhancer sensitivity is dependent on coupling domains or G-protein specificity of the A1 AR. Using six chimaeric A1/A2A ARs, we show that the allosteric effect of PD81,723 is maintained in a chimaera in which the predominant G-protein-coupling domain of the A1 receptor, the 3ICL (third intracellular loop), is replaced with A2A sequence. These chimaeric receptors are dually coupled with Gs and Gi, and PD81,723 increases the potency of N6-cyclopentyladenosine to augment cAMP accumulation with or without pretreatment of cells with pertussis toxin. Thus PD81,723 has similar functional effects on chimaeric receptors with A1 transmembrane sequences that couple with Gi or Gs. This is the first demonstration that an allosteric regulator can function in the context of a switch in G-protein-coupling specificity. There is no enhancement by PD81,723 of Gi-coupled A2A chimaeric receptors with A1 sequence replacing A2A sequence in the 3ICL. The results suggest that the recognition site for PD81,723 is on the A1 receptor and that the enhancer acts to directly stabilize the receptor to a conformational state capable of coupling with Gi or Gs.

scholarly journals Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity

2014 ◽  
Vol 136 (32) ◽  
pp. 11244-11247 ◽  
Author(s):  
Alexander S. Rose ◽  
Matthias Elgeti ◽  
Ulrich Zachariae ◽  
Helmut Grubmüller ◽  
Klaus Peter Hofmann ◽  
...  
Keyword(s):  
G Protein ◽  
Transmembrane Helix ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Coupling Specificity

scholarly journals Characterization of Subtype Selective Cannabinoid CB2 Receptor Agonists as Potential Anti-Inflammatory Agents

2021 ◽  
Vol 14 (4) ◽  
pp. 378
Author(s):  
Yaliang Tang ◽  
Barbara Wolk ◽  
Ryan Nolan ◽  
Caitlin E. Scott ◽  
Debra A. Kendall
Keyword(s):  
G Protein ◽  
Radioligand Binding ◽  
Cb2 Receptor ◽  
G Protein Coupling ◽  
Protein Coupling ◽  
Subtype Selectivity ◽  
Tnf Α ◽  
Antinociceptive Effects ◽  
Anti Inflammatory ◽  
Subtype Selective

Activation of the CB2 receptor has been shown to have anti-inflammatory and antinociceptive effects without causing psychoactive effects. Previously, we reported that the compound ethyl 2(2-(N-(2,3-dimethylphenyl) phenylsulfonamido)acetamido)benzoate (ABK5) is a CB2 subtype selective agonist with anti-inflammatory and antinociceptive effects. In the present study, we tested four ABK5 derivatives, ABK5-1, ABK5-2, ABK5-5, and ABK5-6, to analyze the structure of ABK5 to obtain CB2-selective agonists with higher affinity and efficacy. Affinity, subtype selectivity, and G-protein coupling were determined by radioligand binding assays. Selected compounds were then subjected to evaluation of anti-inflammatory effects using two different cell lines, Jurkat (ABK5-1 and 5-2) and BV-2 cells (ABK5-1), which are models of T cells and microglia, respectively. ABK5-1, ABK5-2, and ABK5-6 had comparable CB2 binding affinity with ABK5 (and stimulated G-protein coupling), while only ABK5-1 and ABK5-2 maintained CB2-subtype selectivity. ABK5-5 did not bind CB2 in the detectable range. RT-PCR and ELISA analysis showed that the two compounds also inhibit IL-2 and TNF-α production, and they were more efficacious than ABK5 in inhibiting TNF-α production. CXCL-12 mediated chemotaxis was also evaluated by the transwell migration assay, and both ABK5-1 and ABK5-2 inhibited chemotaxis with a stronger effect observed in ABK5-1. In the microglia cell line BV-2, ABK5-1 inhibited IL-1β and IL-6 production, which suggests this compound has anti-inflammatory effects through targeting multiple immune cells, and may be a candidate for treatment of inflammation.

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