The NO/cGMP pathway inhibits Rap 1 activation in human platelets via cGMP-dependent protein kinase I
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|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||Online since:||2014-10-06T11:46:37Z||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||Journal:||Thrombosis and Haemostasis||Volume:||93||Issue:||2||Start page:||319||End page:||325||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|
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