Phosphodiesterase-5 and retargeting of subcellular cGMP signaling during pathological hypertrophy.

Both cAMP and cGMP are critical intracellular second messengers regulating fundamental physiological processes in the myocardium, from acute contraction/relaxation to chronic gene expression, cell growth and apoptosis, and cardiac structural remodeling. cAMP is synthesized by adenylate cyclases on activation of G-protein–coupled receptors. cGMP is generated from the cytosolic purine nucleotide GTP by guanylyl cyclases (GCs) with Mg or Mn as cofactors. Two isoforms of GCs exist in vertebrate cells and tissues: a nitric oxide (NO)–sensitive cytosolic or soluble GC (sGC) and atrial natriuretic peptides (NP)–activated, plasma membrane–bound, particulate GC (pGC).1 Once produced, the effects of cGMP occur through 3 main groups of cellular target molecules: cGMP-dependent protein kinases (PKGs), cGMP-gated cation channels, and phosphodiesterases (PDEs). PDEs are metallohydrolases that catalyze the breakdown of cAMP or cGMP into the inactive 5 -AMP, thus modulating the duration and intensity of their intracellular response. PDEs have 11 families (PDE1–PDE11) that are encoded by 21 different genes. More than 80 enzyme variants are generated from multiple promoters and as a consequence of alternative splicing.2 PDE1 through PDE3, PDE10, and PDE11 are dual-specificity esterases because they hydrolyze both cAMP and cGMP; PDE4, PDE7, and PDE8 specifically degrade cAMP; and PDE5, PDE6, and PDE9 hydrolyze cGMP.2 The NH2-terminal portion of the PDE enzyme may undergo phosphorylation/dephosphorylation events, binding of Ca /calmodulin, and allosteric binding of cGMP and can mediate interactions with other proteins. PDE1, PDE3, PDE4, and PDE5 contain phosphorylation sites for various kinases. PDE1 also contains Ca -calmodulin binding sites, and stimuli that increase or decrease intracellular Ca hereby profoundly affecting its activity. PDE2, PDE6, and PDE9 contain allosteric binding sites for cGMP called GAF. The binding of cGMP to GAFB in PDE2 activates the enzyme, whereas the binding of cGMP to GAFA in PDE5 favors PKG-mediated phosphorylation and activation of the enzyme.2 Phosphorylation of PDE5 by PKG serves to increase its cGMP affinity and represents an alternative mode of regulatory feedback inhibition within the cGMP/PKG signaling cascade, thus normalizing levels of cGMP (reviewed elsewhere1). The activation of PKG phosphorylates numerous intracellular proteins that in turn regulate many primary physiological functions such as modulator of vascular tone, vasorelaxation in vascular smooth muscle, endothelial permeability, and cell differentiation and proliferation.3 The PDEs can serve in different functional compartments in cells because they are not colocalized with each other. They are also distributed inside the cell at critical sites and thus regulate local cAMP dynamics in space and time. Such compartmentalization of signaling components allows the extracellular signal to propagate inside the cell along defined and specific pathways within the network.4