The NO/cGMP pathway inhibits Rap 1 activation in human platelets via cGMP-dependent protein kinase I
Files in This Item:
|Danielewski_final-accepted.pdf||3.64 MB||Adobe PDF||Download|
|Title:||The NO/cGMP pathway inhibits Rap 1 activation in human platelets via cGMP-dependent protein kinase I||Authors:||Danielewski, Oliver
Smolenski, Albert P.
|Permanent link:||http://hdl.handle.net/10197/6008||Date:||Feb-2005||Abstract:||The NO/cGMP signalling pathway strongly inhibits agonist-induced platelet aggregation. However, the molecular mechanisms involved are not completely defined. We have studied NO/cGMP effects on the activity of Rap 1, an abundant guanine-nucleotidebinding protein in platelets. Rap 1-GTP levels were reduced by NO-donors and activators of NO-sensitive soluble guanylyl cyclase. Four lines of evidence suggest that NO/cGMP effects are mediated by cGMP-dependent protein kinase (cGKI): (i) Rap 1 inhibition correlated with cGKI activity as measured by the phosphorylation state of VASP, an established substrate of cGKI, (ii) 8-pCPT-cGMP, a membrane permeable cGMP-analog and activator of cGKI, completely blocked Rap1 activation, (iii) Rp-8pCPT-cGMPS, a cGKI inhibitor, reversed NO effects and (iv) expression of cGKI in cGKI-deficient megakaryocytes inhibited Rap1 activation. NO/cGMP/cGKI effects were independent of the type of stimulus used for Rap1 activation. Thrombin-,ADP- and collagen-induced formation of Rap 1-GTP in platelets as well as turbulence-induced Rap 1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap 1 activation induced by the Galpha(i)-coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap 1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin alpha(IIb)beta3, we propose that Rap 1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.||Type of material:||Journal Article||Publisher:||Schatteur||Copyright (published version):||2005 Schatteur||Keywords:||cGMP;Kinase;Nitric oxide;Platelet physiology;Rap1||DOI:||10.1160/TH04-09-0582||Language:||en||Status of Item:||Peer reviewed|
|Appears in Collections:||Medicine Research Collection|
Show full item record
Page view(s) 5062
This item is available under the Attribution-NonCommercial-NoDerivs 3.0 Ireland. No item may be reproduced for commercial purposes. For other possible restrictions on use please refer to the publisher's URL where this is made available, or to notes contained in the item itself. Other terms may apply.