CGMP phosphodiesterase

Pertussis toxin is produced by the bacterium Bordetella pertussis. It covalently modifies G-proteins of the G/Go family (transfer of a ADP-ribose moiety of NAD onto G-protein a-subunits). ADP-ribosylated G-proteins are arrested in their inactive state and, as a consequence, functionally uncoupled from their respective effectors. Examples for pertussis toxin-sensitive cellular responses include the hormonal inhibition of adenylyl cyclases, stimulation ofK+ channels, inhibition of Ca2+ channels and stimulation ofthe cGMP-phosphodiesterase in retinal rods. 

Involved in penile erection sildenafil citrate (Viagra) affects this process by inhibiting a cGMP phosphodiesterase... 

Fox DA, Srivastava D. 1995. Molecular mechanism of the lead-induced inhibition of rod cGMP phosphodiesterase. Toxicol Letters 82/83 263-270. 

Cyclic nucleotides (cAMP and cGMP) are hydrolyzed to destroy the signal. The enzyme that hydrolyzes them is called a phosphodiesterase (more formally, a cAMP or cGMP phosphodiesterase). The signal that activates the synthesis of the cyclic nucleotide will often inhibit the phosphodiesterase. 

D. Activates guanyl cyclase in vascular Inhibits cGMP phosphodiesterase in... 

The pathway activates cGMP phosphodiesterase, which lowers cGMP in response to light. 

In the visual process a light signal is received by the photoreceptors, rhodopsin, of the rod cells which are then converted to the activated state, R. The activated rhodopsin passes the signal on to the cognate G-protein, transducin, which in turn activates the next effector molecule, a cGMP phosphodiesterase. The phophodiesterase hydro-... 

The Ras protein has low intrinsic GTPase activity. This may be increased ca. 10 -fold by the corresponding GTPase-activating protein (see also Chapter 9). In comparison, the intrinsic rate of GTP hydrolysis of transducin is ca. 100-fold higher that that of the Ras protein. The effector molecule next in the reaction chain, the cGMP phosphodiesterase, functions as the GAP here and stimulates GTPase activity of the transducin 100-fold. 

Gtl/ Gt2 Photons (rhodopsin and color opsins in retinal rod and cone cells) t cGMP phosphodiesterase - cGMP (phototransduction)... 

A combination of phentolamine with the nonspecific smooth muscle relaxant papaverine, when injected directly into the penis, may cause erections in men with sexual dysfunction. Long-term administration may result in fibrotic reactions. Systemic absorption may lead to orthostatic hypotension priapism may require direct treatment with an -adrenoceptor agonist such as phenylephrine. Alternative therapies for erectile dysfunction include prostaglandins (see Chapter 18), sildenafil and other cGMP phosphodiesterase inhibitors (see Chapter 12), and apomorphine. 

Dipyridamole is a vasodilator that inhibits platelet function by inhibiting adenosine uptake and cGMP 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. 

Sitaramayya, A. Rhodopsin kinase prepared from bovine rod disk membranes quenches hght activation of cGMP phosphodiesterase in a reconstituted system. Biochemistry, 25, 5460-5468 (1986)... 

Figure 1. Role of nitric oxide, cGMP, phosphodiesterase and sildenafil in erectile function.

Ta-GTP activates cGMP phosphodiesterase (PDE) by binding and removing its inhibitory subunit (I). 

In rod and cone cells of the retina, light activates rhodopsin, which stimulates replacement of GDP by GTP on the G protein transducin. The freed a subunit of transducin activates cGMP phosphodiesterase, which lowers [cGMP] and thus closes cGMP-dependent ion channels in the outer segment of the neuron. The resulting hyperpolarization of the rod or cone cell carries the signal to the next neuron in the pathway, and eventually to the brain. 

Because one molecule of activated cGMP phosphodiesterase can hydrolyze more than 105 molecules of cGMP per second the light response is highly amplified. There is also an earlier stage of amplification. Each molecule of light-activated rhodopsin (R ) is able to catalyze the exchange of GTP for GDP on hundreds of molecules of... 

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