Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.2 (guanylate cyclase)
 8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cyclic GMP (cGMP) made in response to atrial natriuretic peptide (ANP) or nitric oxide (NO) is an important regulator of short-term changes in smooth muscle tone and longer-term responses to chronic drug treatment or proliferative signals. The ability of smooth muscle cells (SMCs) to utilize different combinations of phosphodiesterase (PDE) isozymes allows cGMP to mediate these multiple processes. For example, PDE5 as a major cGMP-hydrolyzing PDE effectively controls the development of smooth muscle relaxation. In order for contraction to occur, PDE5 is activated and cGMP falls. Conversely, blockade of PDE5 activity allows the relaxation cycle to be prolonged and enhanced. A recently shown direct activation of PDE5 by cGMP binding to the GAF A domain suggests that this regulatory site might be a target for new drug development. The calcium surge associated with vasoconstrictor initiated contraction also activates a calcium/calmodulin-dependent PDE (PDE1A). Together, PDE5 and PDE1A lower cGMP sufficiently to allow contraction. Longer term, both PDE5 and PDE1A mRNA are induced by chronic stimulation of guanylyl cyclase. This induction is a major cause of the tolerance that develops to NO-releasing drugs. Finally, high levels of cGMP or cAMP also act as a brake to attenuate the proliferative response of SMCs to many mitogens. After vessel damage, in order for SMC proliferation to occur, the levels of cGMP and cAMP must be decreased. In humans, this decrease is caused in large part by induction of another Ca2+/calmodulin-dependent PDE (PDE1C) that allows the brake to be released and proliferation to start.
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PMID:Cyclic GMP phosphodiesterases and regulation of smooth muscle function. 1293 99

A spinal reflex and the L-arginine-nitric oxide-guanylyl cyclase-cyclic guanosine monophosphate (cGMP) pathway mediate smooth muscle relaxation that results in penile erection. Nerves and endothelial cells directly release nitric oxide in the penis, where it stimulates guanylyl cyclase to produce cGMP and lowers intracellular calcium levels. This triggers relaxation of arterial and trabecular smooth muscle, leading to arterial dilatation, venous constriction, and erection. Phosphodiesterase 5 (PDE5) is the predominant phosphodiesterase in the corpus cavernosum. The catalytic site of PDE5 normally degrades cGMP, and PDE5 inhibitors such as sildenafil potentiate endogenous increases in cGMP by inhibiting its breakdown at the catalytic site. Phosphorylation of PDE5 increases its enzymatic activity as well as the affinity of its allosteric (noncatalytic/GAF domains) sites for cGMP. Binding of cGMP to the allosteric site further stimulates enzymatic activity. Thus phosphorylation of PDE5 and binding of cGMP to the noncatalytic sites mediate negative feedback regulation of the cGMP pathway.
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PMID:Mechanisms of action of PDE5 inhibition in erectile dysfunction. 1522 27

Most effects of the messenger molecule nitric oxide (NO) are mediated by cGMP, which is formed by NO-sensitive guanylyl cyclase (GC) and degraded by phosphodiesterases (PDEs). In platelets, NO elicits a spike-like cGMP response and causes a sustained desensitization. Both characteristics have been attributed to PDE5 activation caused by cGMP binding to its regulatory GAF domain. Activation is paralleled by phosphorylation whose precise function remains unknown. Here, we report reconstitution of all features of the NO-induced cGMP response in human embryonic kidney cells by coexpressing NO-sensitive GC and PDE5. The spike-like cGMP response was blunted when PDE5 phosphorylation was enhanced by additional overexpression of cGMP-dependent protein kinase. Analysis of PDE5 activation in vitro revealed a discrepancy between the cGMP concentrations required for activation (micromolar) and reversal of activation (nanomolar), indicating the conversion of a low-affinity state to a high-affinity state upon binding of cGMP. Phosphorylation even increased the high apparent affinity enabling PDE5 activation to persist at extremely low cGMP concentrations. Our data suggest that the spike-like shape and the desensitization of the cGMP response are potentially inherent to every GC- and PDE5-expressing cell. Phosphorylation of PDE5 seems to act as memory switch for activation leading to long-term desensitization of the signaling pathway.
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PMID:In vivo reconstitution of the negative feedback in nitric oxide/cGMP signaling: role of phosphodiesterase type 5 phosphorylation. 1524 Aug 16