NO/sGC/cGMP/PKG pathways in platelets. (Part in red). Activation of sGC by endogenous NO increases cGMP synthesis. cGMP is involved in regulation of cAMP concentration by PDE2 and PDE3 activation. PDE5 is the main PDE responsible for cGMP degradation. Activated PKG leads to changes in phosphorylation status of numerous proteins and some of them (VASP, IRAG, Rap1B, Rap1Gap2, GRP2, IP3 receptor and others, for details see Section 3) are involved in platelet inhibitory pathways. An alternative hypothesis is presented in blue. However, the expression of any NOS isoform and whether platelets themselves could produce biologically active NO are still under question. In addition, until now, possible involvement of any PKG substrate in platelet stimulatory pathways was not shown (see Section 4.3).