Drug-Target Residence Time-A Case for G Protein-Coupled Receptors

2014 ◽  
Vol 34 (4) ◽  
pp. 856-892 ◽  
Author(s):  
Dong Guo ◽  
Julia M. Hillger ◽  
Adriaan P. IJzerman ◽  
Laura H. Heitman
Keyword(s):  
G Protein ◽  
Residence Time ◽  
Drug Target ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled

scholarly journals The tyrosine phosphatase CD148 is an essential positive regulator of platelet activation and thrombosis

Blood ◽  
2009 ◽  
Vol 113 (20) ◽  
pp. 4942-4954 ◽  
Author(s):  
Yotis A. Senis ◽  
Michael G. Tomlinson ◽  
Stuart Ellison ◽  
Alexandra Mazharian ◽  
Jenson Lim ◽  
...  
Keyword(s):  
G Protein ◽  
Platelet Activation ◽  
Drug Target ◽  
Tyrosine Phosphatase ◽  
Underlying Mechanism ◽  
G Protein Coupled Receptors ◽  
Bleeding Tendency ◽  
Platelet Surface ◽  
Surface Receptors ◽  
G Protein Coupled

Abstract Platelets play a fundamental role in hemostasis and thrombosis. They are also involved in pathologic conditions resulting from blocked blood vessels, including myocardial infarction and ischemic stroke. Platelet adhesion, activation, and aggregation at sites of vascular injury are regulated by a diverse repertoire of tyrosine kinase–linked and G protein–coupled receptors. Src family kinases (SFKs) play a central role in initiating and propagating signaling from several platelet surface receptors; however, the underlying mechanism of how SFK activity is regulated in platelets remains unclear. CD148 is the only receptor-like protein tyrosine phosphatase identified in platelets to date. In the present study, we show that mutant mice lacking CD148 exhibited a bleeding tendency and defective arterial thrombosis. Basal SFK activity was found to be markedly reduced in CD148-deficient platelets, resulting in a global hyporesponsiveness to agonists that signal through SFKs, including collagen and fibrinogen. G protein–coupled receptor responses to thrombin and other agonists were also marginally reduced. These results highlight CD148 as a global regulator of platelet activation and a novel antithrombotic drug target.

Ligand Residence Time at G-protein–Coupled Receptors—Why We Should Take Our Time To Study It

2015 ◽  
Vol 88 (3) ◽  
pp. 552-560 ◽  
Author(s):  
C. Hoffmann ◽  
M. Castro ◽  
A. Rinken ◽  
R. Leurs ◽  
S. J. Hill ◽  
...  
Keyword(s):  
G Protein ◽  
Residence Time ◽  
G Protein Coupled Receptors ◽  
G Protein Coupled
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