TY  - JOUR
A1  - Danielewski, Oliver
A1  - Schultess, Jan
A1  - Smolenski, Albert
T1  - The NO/cGMP pathway inhibits Rap1 activation in human platelets via cGMP-dependent protein kinase I
T2  - Thrombosis and haemostasis
N2  - 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 Rap1, an abundant guanine-nucleotidebinding protein in platelets. Rap1-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) Rap1 inhibition correlated with cGKI activity as measured by the phosphorylation state ofVASP, 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-,ADPand collagen-induced formation of Rap1-GTP in platelets as well as turbulence-induced Rap1 activation in megakaryocytes were inhibited. Furthermore, cGKI inhibited ADP-induced Rap1 activation induced by the G a i -coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling. From these studies we conclude that NO/cGMP inhibit Rap1 activation in human platelets and that this effect is mediated by cGKI. Since Rap1 controls the function of integrin a IIbß 3 , we propose that Rap1 inhibition might play a central role in the anti-aggregatory actions of NO/cGMP.
KW  - cGMP
KW  - Kinase
KW  - Nitric oxide
KW  - Platelet physiology
KW  - Rap1
Y1  - 2014
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/34569
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-345692
SN  - 0340-6245
N1  - This article is not an exact copy of the original published article in Thrombosis and Haemostasis. The definitive publisher-authenticated version of Danielewski O., Schultess J. and Smolenski A. 'The NO/cGMP pathway inhibits Rap 1 activation in human platelets via cGMP-dependent protein kinase I', 93(2): 319-325 is available online at http://th.schattauer.de/en/contents/archive/issue/760/manuscript/4016.html
N1  - 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.
VL  - 93
IS  - 2
SP  - 319
EP  - 325
PB  - Schattauer
CY  - Stuttgart
ER  -