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Direct interaction of calmodulin antagonists with calcium calmodulin dependent cyclic nucleotide phosphodiesterase



Direct interaction of calmodulin antagonists with calcium calmodulin dependent cyclic nucleotide phosphodiesterase



Journal of Biochemistry 96(6): 1721-1726



Trypsin-treated [bovine brain] Ca2+/calmodulin-dependent phosphodiesterase (Ca2+-PDE), which had lost its sensitivity of Ca2+-calmodulin, was inhibited by various calmodulin antagonists, trifluoperazine, chlorpromazine, N-(6-aminohexyl)-5-chloro-1-napthalenesulfonamide (W-7) and aminoalkyl chain analogs of W-7 (A-3, A-4, A-5, I-240, A-6, A-7). These inhibitory effects were less than those on calmodulin-activated Ca2+-PDE. The ability of these compounds to inhibit trypsin-treated Ca2+-PDE. The ability of these compounds to inhibit tryspin-treated Ca2+-PDE correlated well with the inhibitory effect on calmodulin-activated Ca2+-PDE. W-7 inhibited trypsin-treated Ca2+-PDE in a competitive fashion with respect to cGMP and the Ki value was 300 .mu.M. The inhibition of trypsin-treated Ca2+-PDE by W-7 (300 .mu.M) or A-7 (100 .mu.M) was overcome by the addition of excess calmodulin. Trypsin-treated Ca2+-PDE can bind to W-7-coupled cyanogen bromide-activated Sepharose 4B in the presence of 1 mM EGTA[ethylene glycol bis(.beta.-aminoethyl ether)-N,N,N',N'-tetraacetic acid]. These results suggest that Ca2+-PDE possesses a binding site for calmodulin antagonists and that the binding site for these antagonists on this enzyme may be structurally similar to the binding site on calmodulin itself.

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Accession: 005165612

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