PathwayStep529 PathwayStep530 PathwayStep532 PathwayStep531 cGMP is degraded by PDEs cGMP stimulates Protein Kinase G PKG1 phosphorylates BK channels PKG1 phosphorylates IRAG:IP3R1 inhibiting IP3-stimulated Ca2+ release cGMP effects Authored: Akkerman, JW, 2009-06-03 Cyclic guanosine monophosphate (cGMP) is an important secondary messenger synthesized by guanylate cyclases. cGMP has effects on phosphodiesterases (PDE), ion-gated channels, and the cGMP-dependent protein kinases (cGK, Protein Kinase G or PKG). It is involved in regulation of several physiological functions including vasodilation, platelet aggregation and neurotransmission. Elevation of intracellular cGMP activates PKG (Haslam et al. 1999) which regulates several intracellular molecules and pathways including the vasodilator-stimulated phosphoprotein (VASP) (Halbrugge et al. 1990) and the ERK pathway (Hood and Granger 1998, Li et al. 2001). cGMP mediates nitric oxide (NO)-induced vascular smooth muscle relaxation (Furchgott and Vanhoutte 1989). Phosphodiesterase 5 (PDE5) hydrolyzes cGMP; the PDE5 inhibitor sildenafil (Viagra) increases intracellular cGMP and thereby can be used as a treatment for erectile dysfunction (Corbin and Francis 1999). The role of the cGMP and PKG in platelet activation was controversial as increases in platelet cGMP levels were observed in response to both platelet agonists (thrombin, ADP or collagen) and inhibitors (NO donors such as sodium nitroprusside), but it is currently accepted that PKG inhibits platelet activation (Haslam et al. 1999). Consistent with this, nitric oxide (NO) donors that inhibit platelet activation enhance intracellular cGMP (Haslam et al. 1999). cGMP also plays an important stimulatory role in GPIb-IX-mediated platelet activation. Platelet responses to cGMP have been proposed to be biphasic, consisting of an early stimulatory response that promotes platelet activation followed by a delayed platelet inhibition that serves to limit the size of platelet aggregates (Li et al 2003). Edited: Jupe, S, 2010-06-07 Pubmed10318772 Pubmed10605732 Pubmed11522789 Pubmed12526795 Pubmed14597579 Pubmed2154470 Pubmed2545495 Pubmed7913615 Pubmed9722588 Reactome Database ID Release 43418457 Reactome, http://www.reactome.org ReactomeREACT_23767 Reviewed: Kunapuli, SP, 2010-06-07