Cyclic nucleotide phosphodiesterase, calmodulin-dependent

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). 

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. 

The value of X (Eqn. 2) appears to be variable depending on the number of binding subunits for a given enzyme. For example, the cyclic nucleotide phosphodiesterase is frequently described as being a dimeric molecule with each of the two monomers capable of binding one molecule of calmodulin. Similarly, the myosin light chain kinase is reported to bind one calmodulin molecule per subunit (51). Multiple calmodulin binding sites per monomer have not as yet been described for any enzyme with the possible exception of phosphorylase Id kinase. 

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. 

Billingsley, M. L., Polli, J W, Balaban, C. D, and Kincaid, R. L (1990) Developmental expression of calmodulin-dependent cyclic nucleotide phosphodiesterase in rat brain. Dev. Brain Res. 53,253-263. 

Strontium is the most effective element in substituting for calcium in calcium-dependent processes in biological systems.Strontium can induce the conformational changes in calmodulin necessary for stimulation of bovine cyclic nucleotide phosphodiesterase and binding to the calmodulin antagonist trifluoperizine. 

KS-502 (43) was isolated in 1989 [26] and identified as a specific inhibitor of calmodulin-dependent cyclic-nucleotide phosphodiesterase (CaM-PDE). The important roles of CaM and CaM-PDE in cultured cells and living systems underscored the utility of KS-502, perhaps as a valuable biological tool. Its structure comprises an interesting aryl furanoside for which new methodology was devised. 

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