Cyclic GMP-phosphodiesterases

Farber, D. B. From mice to men the cyclic GMP phosphodiesterase gene in vision and disease. Invest. Ophthalmol. Vis. Sci. 36 263-275,1995. 

A further characteristic of this principle is that, if the activity of phosphodiesterase is decreased, the concentration of cyclic GMP will increase to an extent dependent upon the extent of the decrease in activity. This characteristic has been made use of by the pharmaceutical industry. Cyclic GMP has a vasodilatory effect and this is the case for the arterioles that supply blood to the corpus cavemosum in the penis, which controls the erection of the penis. Drugs were developed (e.g. sildenafil) that inhibits cyclic GMP phosphodiesterase and hence increases the cyclic GMP level which resnlts in vasodilation of the arterioles and an increase in the snpply of blood to the spongy tissue of the corpus cavemosum, which expands resulting in erection. This dmg has been found to be effective in some patients snffering from erectile dysfunction. This can be a particular problem in diabetic patients and more elderly men (Chapter 19). 

An increase in the activity of cyclic GMP phosphodiesterase produces a decrease in the concentration of cyclic GMP only if the activity of the enzyme guanyl cyclase remains constant. The principle underlying this requirement is discussed in Chapter 12,... 

Relaxation of smooth mnscles is controlled by the concentration of cyclic GMP in the muscle. This is regulated by the activities of the enzyme that forms cyclic GMP (i.e. gnanyl cyclase) and the enzyme that degrades cyclic GMP, that is, cyclic GMP phosphodiesterase (see Box 12.2). This is analogons to the enzyme system that regulates the concentration of cyclic AMP, by the activities of adenyl cyclase and phosphodiesterase ... 

Antonny, B., Otto-Bruc, A., Chabre, M., and Vuong, T. M. (1993). GTP hydrolysis by purified a-subunit of transducin and its complex with the cyclic GMP phosphodiesterase inhibitor. Biochemistry 32, 8646-8653. 

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cyclic GMP phosphodiesterase activity. Dipyridamole by itself has little or no beneficial effect. Therefore, therapeutic use of this agent is primarily in combination with aspirin to prevent cerebrovascular ischemia. It may also be used in combination with warfarin for primary prophylaxis of thromboemboli in patients with prosthetic heart valves. A combination of dipyridamole complexed with 25 mg of aspirin is now available for secondary prophylaxis of cerebrovascular disease. 

Three distinct G-proteins have been fully characterized. These are transducin (T), which allows rhodopsin to stimulate a high-affinity cyclic GMP phosphodiesterase upon photoactivation in retinal rods Gs, which allows receptors to stimulate the activity of adenylate cyclase and Gh which allows receptors to inhibit adenylate cyclase activity. These three G-proteins contain three non-identical subunits (a, /3 and y). It is their a subunits which provide the binding site for GTP as well as distinct sites for interaction with specific receptor and effector systems and for Mg2+. The /3 subunits associated with all three regulatory proteins are apparently identical although T has a different y subunit. 

Activation of G-proteins by occupied receptors results usually in the dissociation of the G-protein complex, releasing an activated a subunit. In the case of Gs, the activated a subunit interacts with andfactivates the catalytic unit of adenylate cyclase by increasing the affinity of the enzyme for Mg2+, whereas the activated a subunit of transducin stimulates cyclic GMP phosphodiesterase (PDE) activity by causing the dissociation of a y subunit from the PDE, hence relieving an inhibitory effect. G appears to exert its inhibitory effect on adenylate cyclase in two distinct... 

CDK2, cell division kinase 2 cDNA, complementary DNA CDP, cytidine 5 -diphosphate CDPK, Ca2+-dependent protein kinase, calmodulin domain protein kinase CFTR, cystic fibrosis transmembrane conductance regulator cGMP, 3, 5 -c.yclic guanosine monophosphate cGMP PDE, cyclic GMP phosphodiesterase... 

Photoexcited rhodopsin activates transducin, a G-protein, which in turn stimulates cyclic GMP phosphodiesterase this leads to closing of an ion channel, hyperpolarization of the membrane, and a decreased rate of neurotransmitter release (Wald, 1968 Stryer, 1986 Chabre and Deterre, 1989). 

Cyclic GMP-phosphodiesterase 5 -nitrosoglutathione Gel permeation chromatography G-protein-coupled receptor Glycosyl phosphatidylinositol A Golgi-targeting protein domain... 

Rybalkin SD, Yan C, Bornfeldt KE, Beavo JA. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ. Res. 2003 93 280-291. 

Cyclic GMP is metabolised by some phosphodiesterases which also attack cyclic AMP, and these usually possess a higher affinity for cyclic GMP. A specific cyclic GMP phosphodiesterase has recently been identified in rat liver [35]. In mouse epidermis, the enzymatic hydrolysis of cyclic AMP is much more strongly stimulated by low concentrations of Mn " than by those of Mg " in contrast, the hydrolysis of cyclic GMP is exclusively stimulated by Mg " [36]. 

A possible association between the use of methylxanthine consumption and the occurrence of fibrocystic breast disease has been suggested (SEDA-6, 8) (3). It was concluded that in women who are predisposed to fibrocystic disease, methylxanthines are factors in its development. The mechanism of this effect might be an inhibitory action on the activity of cychc AMP and cyclic GMP phosphodiesterases. 

There is another large class of receptors whose occupancy by an agonisf leads to inhibition of adenylate cyclase. These include the tt2 adrenergic receptors, receptors for acetylcholine, adenosine, prostaglandin E2 (Chapter 21), somatostatin, and some receptors for dopamine. Their responses are mediafed by inhibitory proteins Gj, which closely resemble Gg in their sizes, amino acid sequences, and heterotrimeric structures, but which inhibit adenylate cyclase when activated. A clear distinction between the Gg and Gj proteins is evident in the fact that Gg is irreversibly activated by the action of cholera toxin, while G loses its ability to respond to occupied receptors when modified by the action of Pertussis toxin (Box 11-A). A specialized heterotrimeric G protein known as transducin mediates the light-induced activation of a cyclic GMP phosphodiesterase in the retina " (see Chapter 23). Its a subunit is designated aj. The related gustducin is found in taste buds. ... 

Ruckstuhl, M. Beretz, A. Anton, R. Landry, Y., Flavonoids are selective cyclic GMP phosphodiesterase inhibitors, Biochem. Pharmacol, 1979, 28, 535-538. 

The visual transduction system of retinal membranes contains a plethora of prenylated proteins. One of the prenylated components is a protein called transducin. This protein is a member of a family of G proteins that contain three distinct subunits (a, P, and y) and function in mediating signal transduction from cell membrane receptors to downstream effector proteins. In the case of visual transduction, photoactivation of rhodopsin leads to a conformational change that is sensed by transducin. In the absence of photoactivation of rhodopsin, transducin exists in a resting state in which Gt)P is bound to its a-subunit. Photoactivated rhodopsin catalyzes the exchange of GDP bound to transducin with GTP. This GTP-bound activated transducin then stimulates the enzymatic activity of another membrane-bound protein termed cyclic GMP phosphodiesterase. The latter... 

The cyclic GMP phosphodiesterase described above is also prenylated. This enzyme is composed of four subunits (a, P, and two-y subunits). Recent studies have shown that the a-subunit contains a C-terminal farnesyl-cysteine methyl ester, whereas the P-subunit is geranylgeranylated (Anant et al 1992). The C-terminal region of the a-subunit has also been shown to be important for attachment of the phosphodiesterase to the retinal membranes. 

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