Brain phosphodiesterase

Pseudodistomins A and B were cytotoxic against L1210 (IC50 = 2.5 pg/ml and 0.4 pg/ml, respectively) and L5178Y (IC50 = 2.4 pg/ml and 0.7 pg/ml, respectively) murine leukemia cells [459], This study found that both 186c,d were also potent inhibitors of calmodulin-activated brain phosphodiesterase (IC50 = 3 x 10 M). 

A number of metabolites which appear to be derived from Tyrosine, Dopa, or Topa residues and to have similar biogenetic origins to the tunichromes have been reported. Rigidin (48), isolated from the Okinawan marine tunicate Eudistoma c.f. rigida exhibited calmodulin antagonistic activity with an IC50 of 5 x lO M against calmodulin-activated brain phosphodiesterase [42]. Some other pyrrolo[2,3d]pyrimidine-2,4-diones which have been synthesised have shown weak affinity for the benzodiazepine receptor. 

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. 

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