Calmodulin-dependent phosphodiesterase

Calmodulin-dependent phosphodiesterase = Dibutyryl cyclic AMP = Acyl carrier protein = S-Adenosyl-L-methionine = S-Adenosyl-I-homocysteine... 

Both calmodulin and a calcium- and calmodulin-dependent phosphodiesterase activity occur in dispersed bovine parathyroid cells (20.). Some of the phenothiazines blocking the dopamine receptor in this tissue inhibit the interaction between calmodulin and the calmodulin-dependent phosphodiesterase. A series of experiments have tested the possibility that calmodulin might play a role in the effects of these agents on the parathyroid gland. The dopamine antagonists examined were weak inhibitors of calmodulin-stimulated phosphodiesterase activity (Table II). 

The stereospecific dopaminergic antagonists (-) and (+) butaclamol and cis- and trans-flupenthixol were of equal potency in their effects on calmodulin-dependent phosphodiesterase activity. This contrasts with the marked difference in the potency of each pair of stereoisomers as dopamine antagonists. It appears unlikely that the calmodulin-dependent phosphodiesterase activity (and by inference calmodulin) plays any role in the actions of dopaminergic antagonists upon the bovine parathyroid gland. 

Polli JW, Kincaid RL (1992) Molecular cloning of DNA encoding a calmodulin-dependent phosphodiesterase enriched in striatum. Proc Natl Acad Sci USA 59 11079-11083. 

Polli JW, Kincaid RL (1994) Expression of a calmodulin-dependent phosphodiesterase isoform (PDE1B1) correlates with brain regions having extensive dopaminergic innervation. J Neurosci 74 1251-1261. 

An azido-12->I-calmodulin derivative suitable for labeling calmodulin binding proteins by photoaffinity has recently been described (45). Azido-calmodulin retained the ability to interact with and activate the calmodulin-dependent phosphodiesterase in a Ca +-dependent manner. Upon photolysis calmodulinbinding subunits of the enzyme formed 1 1 crosslinked complexes with the derivative. Crosslinked products were not obtained with incubations performed with EGTA or in large excess of unmodified calmodulin. Following photoaffinity labeling the calmodulin-dependent ATPase from red cells was found to be irreversibly activated by the derivative. 

Stellettamide A (99), an unusual indolizidine alkaloid originally isolated from Stelletta sp. as an antifungal and cytotoxic compound,was found to inhibit Ca /calmodulin-dependent phosphodiesterase and... 

Ca -Mg )-ATPase with IC50 values of 52 and lOOpmoll respectively. Three related alkaloids stellettazole A (100) " and bistellettadines A (101) and B (102) from the same sponge showed moderate inhibitory activity against Ca /calmodulin-dependent phosphodiesterase (stellettazole A 45% inhibition at 100p.moll bistellettadines A and B 40% inhibition at lOOpmolP ). 

In most tissues, a calmodulin-dependent phosphodiesterase has been found which hydrolyses both cyclic AMP and cyclic GMP [3]. The activity of the phosphodiesterase in the presence of calmodulin is inhibited by several of the calcium channel blockers. Nimodipine, nicardipine, felodipine, nisoldipine and nitrendipine are much more potent inhibitors than verapamil, D600 or diltiazem [ 171, 175-177]. Half-maximal inhibition of phosphodiesterase activity is seen with 2-20 jiM concentrations of the 1,4-dihydropyridines, whereas more than 100 verapamil or diltiazem is required to produce 50% inhibition [ 171, 176 ]. The effects of nifedipine in different studies have been inconsistent. In some studies, low concentrations of nifedipine have been found to inhibit calmodulin-activated phosphodiesterase [ 176, 177], but in other investigations nifedipine has had only a slight inhibitory effect on phosphodiesterase at up to 10 /xM [175, 178]. This discrepancy may be due to different sensitivities of phosphodiesterases from varying sources to nifedipine. There are also calmodulin-insensitive forms of phosphodiesterase whose activity is inhibited by verapamil, nimodipine, nicardipine, nifedipine and diltiazem [171,177]. 

As part of their extensive survey of the behaviour of cAMP-dependent systems with analogues of cAMP, Jastorff and his group have compared the substrate specificity of cAMP phosphodiesterase from Dictyostelium discoi-deum with that from beef heart (Van Haastert et ai, 1983). The former is a cell-surface enzyme with low specificity for cAMP, the latter a low- T, (high-affinity) calmodulin-dependent phosphodiesterase. Twenty-five analogues were studied, but our interest lies with the phosphorothioate diastereomers of cAMP(S). The Sp diastereomer is shown to be hydrolysed faster by at least two orders of magnitude than the Rp diastereomer by the beef-heart enzyme, despite similar relative values. The mechanistic interpretation of this phenomenon is based on the theoretical calculations of Van Ool and Buck, and led Jastorff to support Eckstein s double-displacement mechanism, involving pseudorotation (Scheme 37d cf. 37b). 

Richard G, Federolf G, Habermann E (1985) The interaction of aluminum and other metal ions with caldum-calmodulin-dependent phosphodiesterase. Arch Toxicol 57 257-259... 

In addition, vinpocetine selectively inhibits a specific calcium, calmodulin-dependent cycHc nucleotide phosphodiesterase (PDF) isozyme (16). As a result of this inhibition, cycHc guanosine 5 -monophosphate (GMP) levels increase. Relaxation of smooth muscle seems to be dependent on the activation of cychc GMP-dependent protein kinase (17), thus this property may account for the vasodilator activity of vinpocetine. A review of the pharmacology of vinpocetine is available (18). 

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. 

Hashimoto,Y., Sharma, R. K. and Soderling, T. R. Regulation of Ca+2/calmodulin-dependent cyclic nucleotide phosphodiesterase by the autophosphorylated form Ca+2/ calmodulin-dependent protein kinase II. J. Biol. Chem. 264 10884-10887,1989. 

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). 

Rowlands MG, Parr IB, McCague R, Jarman M, Goddard PM (1990) Variation of the inhibition of calmodulin dependent cyclic AMP phosphodiesterase amongst analogues of tamoxifen correlations with cytotoxicity. Biochem Pharmacol 40 283-289... 

Mata R, Gamboa A, Macias M, Santillan S, UUoa M, Gonzalez MC, Effect of selected phytotoxic agents from Guanomyces polythrix on the calmodulin-dependent activity of the enzymes cAMP phosphodiesterase and NAD-kinase, JAgricFood Chem 51 4559 562, 2003. 

Upon binding calcium ions, the small acidic protein known as calmodulin can activate enzymes by binding to a wide variety of proteins containing cahnodulin-binding domains. Such proteins include cAMP phosphodiesterase, calmodulin-dependent nitric oxide synthase, calmodulin kinases, the plasma membrane calcium pump, calcineurin, and calmodulin-dependent inositol-(l,4,5)-trisphosphate 3-kinase. See also Activation Autoinhibition... 

The second messenger molecules Ca2+ and cyclic AMP (cAMP) provide major routes for controlling cellular functions. In many instances, calcium (Ca2+) achieves its intracellular effects by binding to the receptor protein calmodulin. Calmodulin has the ability to associate with and modulate different proteins in a Ca2+-dependent and reversible manner. Calmodulin-dependent cyclic nucleotide phosphodiesterase (CaMPDE, EC 3.1.4.17) is one of the key enzymes involved in the complex interactions that occur between the cyclic-nucleotide and Ca2+ second messenger systems (see Figure 13.2). CaMPDE exists in different isozymic forms, which exhibit distinct molecular and catalytic properties. The differential expression and regulation of individual phosphodiesterase (PDE) isoenzymes in different tissues relates to their function in the body. 

For those interested in the pharmacology of calmodulin antagonists or physicochemical studies on calmodulin structure, Vincenzi (1981) and Krebs (1981) are suggested. Reviews that include substantial sections on the adenylate cyclase-phosphodiesterase systems and calmodulin or on calmodulin-dependent protein phosphorylations can be found in Cheung (1981), Brostrom and Wolf (1981), and Stoclet (1981). 

Figure 7.2. Some intracellular processes that may be affected by calcium channel blocking drugs. Calcium channel blocking drugs inhibit calmodulin-dependent sarcolemmal Ca2 -A TPase (7), myosin light-chain kinase (MLCK) (2) and phosphodiesterase (PDE) (7). Passive Na -Ca2 exchange (4) may also be inhibited, whilst (Na +K )-ATPase (J) is stimulated. Ca2 release from mitochondria (MIT) in exchange for Na ( ) may be inhibited, but the effect of calcium channel blocking drugs on Ca2 uptake into sarcoplasmic reticulum (SR) via Ca2 -ATPase (7) is variable.

Calmodulin-binding peptides. Peptides that inhibit calmodulin-dependent cyclic nucleotide phosphodiesterase have been isolated from peptic digests of a i-casein (a i plus and identified as aj2-CN fl64-179, s2-CN fl83-206 and a j-CN fl83-207. The physiological significance of these peptides is unknown. 

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