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 Mg2+ or Mn2+ 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 Ca2+/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 Ca2+-calmodulin binding sites, and stimuli that increase or decrease intracellular Ca2+ 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 …