Co-activation of Gi and Gq proteins exerts synergistic effect on human platelet aggregation through activation of phospholipase C and Ca2+ signalling pathways.
Our previous studies have shown that subthreshold concentrations of two platelet agonists exert synergistic effects on platelet aggregation. Here we studied the mechanism of synergistic interaction of 5-hydroxytryptamine (5-HT) and epinephrine mediated platelet aggregation. We show that 5-HT had no or little effect on aggregation but it did potentiate the aggregation response of epinephrine. The synergistic interaction of 5-HT (1-5 microM) and epinephrine (0.5-2 microM) was inhibited by alpha2-adrenoceptor blocker (yohimbine; IC50= 0.4 microM), calcium channel blockers (verapamil and diltiazem with IC50 of 10 and 48 mM, respectively), PLC inhibitor (U73122; IC50=6 microM) and nitric oxide (NO) donor, SNAP (IC50=1.6 microM)). The data suggest that synergistic effects of platelet agonists are receptor-mediated and occur through multiple signalling pathways including the activation PLC/Ca2+ signalling cascades.
Shah
B H
BH
Department of Physiology and Pharmacology, The Aga Khan University, Karachi, Pakistan.
Siddiqui
A
A
Qureshi
K A
KA
Khan
M
M
Rafi
S
S
Ujan
V A
VA
Yakoob
M Y
MY
Yaqub
Y
Y
Rasheed
H
H
Saeed
S A
SA
D015153:Blotting, Western; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D004357:Drug Synergism; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004837:Epinephrine / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D002121:Calcium Channel Blockers; D004791:Enzyme Inhibitors; D012701:Serotonin; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D004837:Epinephrine