Nuclear signaling in smooth muscle cells: cyclic nucleotide phosphodiesterase 1A moves in.

The second messenger cyclic GMP (cGMP) mediates signaling in the nervous system, genitourinary system, and the gastrointestinal tract. In the cardiovascular system, cGMP regulates vasorelaxation, vascular remodeling, platelet activation, and cardiac contractility. The ability of cGMP to regulate such a large number of temporally and spatially disparate processes is attributable to the many different isozymes that exist for synthesis and degradation of cGMP. These enzymes exhibit different subcellular localization and mechanisms of activation. Thus, cGMP is synthesized from GTP by both soluble and particulate forms of guanylyl cyclase. Soluble guanylyl cyclases are heterodimeric cytosolic enzymes that consist of and subunits. There are several isoforms of the and subunit, 1 1 being the most abundant combination in mammalian tissues.1–3 Soluble guanylyl cyclase is activated by nitric oxide (NO) and NO-releasing drugs. Particulate forms of guanylyl cyclase, on the other hand, are transmembrane proteins that are activated by the natriuretic peptides ANP, BNP, and CNP.4 Similarly, cGMP is degraded by a large number of cyclic nucleotide phosphodiesterases (PDEs). To date, 21 different PDE genes divided among 11 gene families have been identified in mammals. Most PDE families contain more than one gene, and most genes code for more than one mRNA. Although some PDE gene families hydrolyze cAMP exclusively (PDE4, PDE7, PDE8), many of these enzymes hydrolyze cGMP, or both cAMP and cGMP.5 PDE5 is the major cGMP-specific PDE gene family in some cell types. Other cGMP-hydrolyzing PDE gene families include PDE1, PDE2, PDE6, PDE9, PDE10, PDE11, and possibly PDE3.6 Any particular cell type typically expresses several different guanylyl cyclases and cGMP-hydrolyzing PDEs, which provide the cell with tools to precisely regulate cGMP synthesis and hydrolysis in different subcellular compartments and following exposure to different stimuli. Many of the effects of cGMP are mediated by cGMPdependent protein kinases.7 The cGMP-dependent kinases (cGK or PKG) are serine/threonine kinase dimers encoded by two genes in mammals, cGKI and cGKII. Binding of cGMP to cGK induces a conformational change and exposure of the catalytic center of the molecule, which is then able to phosphorylate a number of substrates in vivo. These substrates include ion channels, G proteins, cytoskeletal proteins, and transcriptional regulators.7–8 In addition, cGMP exerts effects that are cGK-independent. For example, cGMP can regulate cAMP-dependent protein kinases (PKA) through direct or indirect mechanisms, as well as ion channels and guanine nucleotide exchange factors.