MK4MDD

BioCarta Pathway Report

Basic Information
ID NO1_PATHWAY
Name no1 pathway
Brief Description Actions of Nitric Oxide in the Heart
Full Description Nitric oxide (NO) has a number of important physiological actions in the cardiovascular system. In the heart, NO plays role in keeping the vessels patent via vasodilation and prevention of platelet aggregation. It also plays an important role in regulating the force and rate of contraction. In vivo NO is released by shear stress of ligands that increase intracellular Ca2+ in endothelial cells. The increase intracellular Ca2+ activates nitric oxide synthase III (NOSIII) by promoting the binding of Ca/Calmodulin to the enzyme. NOSIII, which is resident in the Golgi complex, is transported together with caveolin-1 to the caveolae at the plasma membrane via vesicles. Shear stress signals via a potassium channel and the cytoskeleton, which results in tyrosine phosphorylation of specific proteins, activation of phosphatidylinositol 3-kinase, and subsequently in activation of Akt kinase. Akt activation by shear stress but also by VEGF activates NOSIII by serine phosphorylation, which increases the affinity of NOSIII for calmodulin. After agonist binding at the plasma membrane, NOSIII-activating receptors translocate to caveolae. VEGF receptor signals via its tyrosine kinase domain. Furthermore, agonist receptors activate calcium channels of the endoplasmic reticulum (ER) via phospholipase C and inositol 1,4,5-trisphosphate. This calcium flux induces binding of calmodulin to NOSIII, whereas the NOSIII-caveolin-1 interaction is disrupted. At the same time, NOSIII is translocated into the cytosol. On binding of calmodulin, NOSIII generates NO, is enhanced by the interaction with Hsp90. Once activated, NOSIII catabolizes L-arginine to NO, which diffuses out of the cell. NO stimulates guanylate (G-) cyclase and increases cGMP levels. cGMP activates cGMP-dependent protein kinase (PKG), cGMP-inhibited phosphodiesterase (PDEIII), and cGMP-stimulated phosphodiesterase (PDEII). PKG may reduce the force and rate of contraction, possibly by phosphorylating troponin I or by phosphorylating phospholamban. PDEIII is inhibited by the increases in cGMP brought about by NO. This may result in an increase in cAMP and cAMP-dependent protein kinase (PKA). PKA in turn activates Ca2+ channels, countering the effects of PKG. In contrast, cGMP may stimulate PDEII, reduce cAMP levels and PKA activity, and thereby reduce Ca2+ channel activity. Ach, acetylcholine. CAT-1, cationic amino acid transporter.

NO1_PATHWAY related genes in MK4MDD (count: 11)
Approved Symbol Approved Name Type No. of Studies (Positive/Negative)
CALM2 calmodulin 2 (phosphorylase kinase, delta) Literature-origin 1(1/0)
PRKAR2A protein kinase, cAMP-dependent, regulatory, type II, alpha Literature-origin 1(1/0)
VEGFA vascular endothelial growth factor A Literature-origin 1(1/0)
RYR2 ryanodine receptor 2 (cardiac) Literature-origin 1(1/0)
PDE3A phosphodiesterase 3A, cGMP-inhibited Literature-origin 1(1/0)
CALM1 calmodulin 1 (phosphorylase kinase, delta) Literature-origin 1(1/0)
NOS3 nitric oxide synthase 3 (endothelial cell) SNP mapped; Protein mapped 0(0/0)
BDKRB2 bradykinin receptor B2 SNP mapped 0(0/0)
PRKAR1A protein kinase, cAMP-dependent, regulatory, type I, alpha Literature-origin; Protein mapped 1(1/0)
PRKAR2B protein kinase, cAMP-dependent, regulatory, type II, beta Literature-origin 1(1/0)
PRKACB protein kinase, cAMP-dependent, catalytic, beta Protein mapped 0(0/0)