Enhanced Detection of Receptor Constitutive Activity in the Presence of Regulators of G Protein Signaling: Applications to the Detection and Analysis of Inverse Agonists and Low-Efficacy Partial Agonists

2002 ◽  
Vol 61 (5) ◽  
pp. 1211-1221 ◽  
Author(s):  
Philip J. Welsby ◽  
Elaine Kellett ◽  
Graeme Wilkinson ◽  
Graeme Milligan
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Constitutive Activity ◽  
Protein Signaling ◽  
Inverse Agonists ◽  
Partial Agonists

Focus Issue: New insights in GPCR to G protein signaling

2016 ◽  
Vol 9 (423) ◽  
pp. eg6-eg6 ◽  
Author(s):  
Nancy R. Gough
Keyword(s):  
G Protein ◽  
G Protein Signaling ◽  
Constitutive Activity ◽  
Protein Signaling ◽  
Polarized Growth ◽  
G Protein Coupling ◽  
Α Subunit ◽  
Protein Coupling ◽  
G Protein Coupled ◽  
Orphan Gpcr

This Focus Issue highlights new discoveries at the level of the receptor, the α subunit, and the βγ subunit and spans research in yeast on polarized growth and G protein–coupled receptor (GPCR) trafficking, in mice on an orphan GPCR with constitutive activity, and a disease-causing mutation in an α subunit that results in inappropriate GPCR–G protein coupling.

scholarly journals Distinct cortical and striatal actions of a β-arrestin–biased dopamine D2 receptor ligand reveal unique antipsychotic-like properties

2016 ◽  
Vol 113 (50) ◽  
pp. E8178-E8186 ◽  
Author(s):  
Nikhil M. Urs ◽  
Steven M. Gee ◽  
Thomas F. Pack ◽  
John D. McCorvy ◽  
Tama Evron ◽  
...  
Keyword(s):  
G Protein ◽  
Dopamine D2 Receptor ◽  
D2 Receptor ◽  
G Protein Signaling ◽  
Protein Signaling ◽  
Partial Agonists ◽  
Elevated Expression ◽  
Fast Spiking ◽  
Cortical Dysfunction ◽  
G Protein Coupled

The current dopamine (DA) hypothesis of schizophrenia postulates striatal hyperdopaminergia and cortical hypodopaminergia. Although partial agonists at DA D2 receptors (D2Rs), like aripiprazole, were developed to simultaneously target both phenomena, they do not effectively improve cortical dysfunction. In this study, we investigate the potential for newly developed β-arrestin2 (βarr2)-biased D2R partial agonists to simultaneously target hyper- and hypodopaminergia. Using neuron-specific βarr2-KO mice, we show that the antipsychotic-like effects of a βarr2-biased D2R ligand are driven through both striatal antagonism and cortical agonism of D2R-βarr2 signaling. Furthermore, βarr2-biased D2R agonism enhances firing of cortical fast-spiking interneurons. This enhanced cortical agonism of the biased ligand can be attributed to a lack of G-protein signaling and elevated expression of βarr2 and G protein-coupled receptor (GPCR) kinase 2 in the cortex versus the striatum. Therefore, we propose that βarr2-biased D2R ligands that exert region-selective actions could provide a path to develop more effective antipsychotic therapies.

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