Phosphodiesterases brain

Calmodulin, a calcium binding protein, is involved in Ca2+-dependent regulation of several synaptic functions of the brain synthesis, uptake and release of neurotransmitters, protein phosphorylation and Ca+2 transport. It reacts with TET, TMT and TBT which then inactivates enzymes like Ca+2-ATPase and phosphodiesterase. In vitro studies indicated TBT was greater at inhibiting calmodulin activity than TET and TMT, whereas in vivo the order was TET > TMT > TBT. This may be due to the greater detoxification of TBT (66%) in the liver before moving to other organs30,31. 

Sharma, R. and Wang, J. H. Differential regulation of bovine brain calmodulin-dependent cyclic nucleotide phosphodiesterase isozzymesdby cyclic AMP-dependent protein kinase and calmodulin-dependent protein phosphatase. Proc. Natl Acad. Sci. U.S.A. 82 2603-2607,1986. 

Repaske, D., Corbin, J. G., Conti, M. and Goy, M. F. A cyclic GMP-stimulated cyclic nucleotide phosphodiesterase gene is highly expressed in the limbic system of the rat brain. Neuroscience 56 673-686,1993. 

McPhee, I., Pooley, L., Lobban, M., Bolger, G. and Houslay, M. D. Identification, charactirization and regional distribution in brain of RPDE-6 (RNPDE4A5), a novel splice variant of the PDE4A cyclic AMP phosphodiesterase family. Biochem. J. 310 965-974,1995. 

Miro, X., Perez-Torres, S., Palacios, J. M., Puigdomenech, P. and Mengod, G. Differential distribution of cAMP-specific phosphodiesterase 7A mRNA in rat brain and peripheral organs. Synapse A0 201-214, 2001. 

Van Staveren, W., Steinbusch, H. W. M., Markerink-Van Ittersum, M. et al. mRNA expression patterns of the cGMP-hydrolysing phosphodiesterases types 2, 5, and 9 during development of the rat brain. /. Comp. Neurol. 467 566-580, 2003. 

Because of its ability to bind CaM, tamoxifen can increase cyclic AMP surges by inhibiting cyclic AMP hydrolysis by the Ca2+-calmodulin-dependent cyclic nucleotide phosphodiesterase (Fanidi et al. 1989 Rowlands et al. 1990). In bovine brain preparations, tamoxifen appears to act as a competitive inhibitor of calmodulin-activated phosphodiesterase with an IC50 of 2 p,M, similar to the value reported for trifluoperazine under the same experimental conditions (Lam 1984). 

Mehorta and coworkers (1989) observed that isolated fractions of brain and heart cells from rats orally administered 0.5-10 mg endrin/kg showed significant inhibition of Ca+2 pump activity and decreased levels of calmodulin, indicating disruption of membrane Ca+2 transport mechanisms exogenous addition of calmodulin restored Ca+2-ATPase activity. In vitro exposure of rat brain synaptosomes and heart sarcoplasmic reticuli decreased total and calmodulin-stimulated calcium ATPase activity with greater inhibition in brain preparations (Mehorta et al. 1989). However, endrin showed no inhibitory effects on the calmodulin-sensitive calcium ATPase activity when incubated with human erythrocyte membranes (Janik and Wolf 1992). In vitro exposure of rat brain synaptosomes to endrin had no effect on the activities of adenylate cyclase or 3, 5 -cyclic phosphodiesterase, two enzymes associated with synaptic cyclic AMP metabolism (Kodavanti et al. 1988). 

Kodavanti PR S, Mehrotra BD, Cherry SC, et al. 1988. Effect of selected insecticides on rat brain synaptosomal adenylate cyclase and phosphodiesterase. J Toxicol Environ Health 25(2) 207-215. 

Vig PJS, Mehrotra BD, Desaiah D. 1990b. Holothurin An activator of bovine brain 3 -5 phosphodiesterase. Res Commun Chem Pathol Pharmacol 67(3) 419-42. 

Macovschi 0, Prigent AF, Nemoz G, Pacheco FI. (1987). Effects of an extract of Ginkgo biloba on the 3, 5 -cyclic AMP phosphodiesterase activity of the brain of normal and triethyltin-intoxicated rats. J Neurochem. 49(1) 107-14. 

Davies DB, Holub BJ. 1983. Comparative effects of organophosphorus insecticides on the activities of acetylcholinesterase, diacylglycerol kinase, and phosphatidylinositol phosphodiesterase in rat brain microsomes. Pesti Biochem Physiol 20 92-99. 

Appleman, M. M., Thompson, W. J. (1971) Multiple cyclic nucleotide phosphodiesterase activities from rat brain. Biochemistry 10(2), 311-316. 

The TET-induced inhibitory influence on cyclic 3 ,5 -AMP phosphodiesterase (PDE) activities precedes edema formation in the rat brain [74]. lb clarify the mechanism of the protective action of EGb against TET-toxidty in rats, in vitro and ex vivo effects of EGb on PDE activities of cerebral tissue were investigated [75]. Higher concentrations of EGb (5-250 mg/L) inhibited the PDE activity in the brain in normal rats, whereas lower concentrations (0.25-4.0 mg/L) of EGb enhanced the activity of the enzyme. The inhbitory effect of TET on the high affinity PDE activity (measured with 0.25 ftM cyclic AMP) of the brain was diminished in the presence of low EGb concentrations. Furthermore, preventive and curative treatment of 1 El-poisoned rats with EGb (100 mg/kg, p.o., for 7 days) prevented both the formation of edema and the fall of PDE activity induced by TET alone. These results suggested the antiedema action of EGb might be partly associated with its modulating influences on cellular cyclic AMP levels via activation of membrane-bound PDE. 

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. 

In addition to the proposed regulatory role of ATP and pyrophosphate, some possibility exists that 3, 5 -cyclic phosphate diesterase is under physiological control. Such ideas arose through observations of Cheung (43, 62) that the partially purified enzyme from beef brain was markedly activated by snake venom. The stimulatory factor was labile at extreme pH it was not dialyzable and appeared to be a protein. A similar activating factor is also present in brain tissue (63) and is removed during purification of the diesterase. It seems to interact stoichiometrically with the enzyme. The activator is destroyed by trypsin and is not proteolytic itself. The precise role of this protein in regulating the phosphodiesterase in vivo is not yet established, however. 

Normally, the desire to have sexual relations is a powerful message sent from the brain down the spinal cord and through peripheral nerves to smooth muscle cells in the penis, triggering them to produce sufficient nitric oxide to form all the cyclic GMP necessary to create an erection (Fig. 14—11). The cyclic GMP lasts long enough for sexual intercourse to occur, but then phosphodiesterase (type V in the penis) eventually breaks down the cGMP (Fig. 14—5), and the erection is lost (called detumescence). 

Table 8 shows that at concentrations of 10-7 — 10 8M l-(chloromethyl)sila-trane does not affect phosphodiesterase of the rat brain and monoamine oxidase of the rat liver. At the same time, at 10 4M concentration the preparation weakly inhibits the acetylcholinesterase of the rat brain. Therefore, 1-(chloromethyl)sila-trane may be expected to produce a gentle stimulatory effect on the processes in the central and peripheral nervous system which are mediated by acetylcholine. l-(Chloromethyl)silatrane activates mildly the preparation of summarized ATP values of the rat liver. No reaction is observed with SH-groups of glutathione. 

Picq M, Dubois M, Prigent AF, Nemoz G, Pacheco H. 1989. Inhibition of the different cyclic nucleotide phosphodiesterase isoforms separated from rat brain by flavonoid compounds. Biochem Int 18 47-57. 

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