scholarly journals Label-Free Whole Cell Biosensing for High-Throughput Discovery of Activators and Inhibitors Targeting G Protein-Activated Inwardly Rectifying Potassium Channels

ACS Omega ◽  
2018 ◽  
Vol 3 (11) ◽  
pp. 14814-14823 ◽  
Author(s):  
Katrin M. Krebs ◽  
Eva M. Pfeil ◽  
Katharina Simon ◽  
Manuel Grundmann ◽  
Felix Häberlein ◽  
...  
Keyword(s):  
Potassium Channels ◽  
G Protein ◽  
High Throughput ◽  
Label Free ◽  
Whole Cell ◽  
Inwardly Rectifying Potassium Channels ◽  
Inwardly Rectifying

scholarly journals G-protein–gated inwardly rectifying potassium channels regulate ADP-induced cPLA2 activity in platelets through Src family kinases

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3027-3034 ◽  
Author(s):  
Haripriya Shankar ◽  
Bryan N. Kahner ◽  
Janani Prabhakar ◽  
Parth Lakhani ◽  
Soochong Kim ◽  
...  
Keyword(s):  
Potassium Channels ◽  
G Protein ◽  
P2y Receptors ◽  
Null Mouse ◽  
Channel Blockers ◽  
Functional Responses ◽  
Kinase Activation ◽  
Girk Channel ◽  
Inwardly Rectifying Potassium Channels ◽  
Inwardly Rectifying

Abstract ADP-induced TXA2 generation requires the costimulation of P2Y1, P2Y12, and the GPIIb/IIIa receptors. Signaling events downstream of the P2Y receptors that contribute to ADP-induced TXA2 generation have not been clearly delineated. In this study, we have investigated the role of G-protein–gated inwardly rectifying potassium channels (GIRKs), a recently identified functional effector for the P2Y12 receptor, in the regulation of ADP-induced TXA2 generation. At 10-μM concentrations, the 2 structurally distinct GIRK channel blockers, SCH23390 and U50488H, caused complete inhibition of ADP-induced cPLA2 phosphorylation and TXA2 generation, without affecting the conversion of AA to TXA2 or ADP-induced primary platelet aggregation in aspirin-treated platelets. In addition, Src family kinase selective inhibitors abolished 2MeSADP-mediated cPLA2 phosphorylation and TXA2 generation. Furthermore, these GIRK channel blockers completely blocked Gi-mediated Src kinase activation, suggesting that GIRK channels are upstream of Src family tyrosine kinase activation. In weaver mouse platelets, which have dysfunctional GIRK2 subunits, ADP-induced TXA2 generation was impaired. However, we did not observe any defect in 2MeSADP-induced platelet functional responses in GIRK2-null mouse platelets, suggesting that functional channels composed of other GIRK subunits contribute to ADP-induced TXA2 generation, via the regulation of the Src and cPLA2 activity.

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