Les phosphodiestérases des nucléotides cycliques

Abstract

Cyclic nucleotide phosphodiesterases (PDE) are classified into five families (PDE I to V) according to their primary sequence, their substrate specificities and their sensitivities to different modulators. PDE I, PDE II and PDE III can hydrolyze both cAMP and cGMP. Calmodulin stimulates PDE I activity. Cyclic GMP can itself modulate the hydrolysis of cAMP. It stimulates the hydrolysis of cAMP through PDE II, whereas it inhibits it through PDE III. The modulation of cAMP level by cGMP might explain either the synergistic or the opposite effects of cAMP and cGMP on some biological functions. PDE III are inhibited by some cardiotonic drugs (milrinone...) and are regulated in some tissues by a mechanism of phosphorylation. PDE IV selectively hydrolyze cAMP and are inhibited by rolipram. When both PDE III and PDE IV coexist in a cell type, PDE III might be involved in the regulation of basal level of cAMP whereas PDE IV might regulate higher level of cAMP. This might be due to the difference in the K(m) value of PDE III and PDE IV for cAMP. The last family, PDE V, specifically hydrolyzes cGMP and is involved in the regulation of smooth muscle relaxation and visual transduction. Selective PDE inhibitors are useful as pharmacological tools to increase cAMP or cGMP levels in target cells and, by this way, they arc potential therapeutic agents for the treatment of clinical disorders such as heart failure depression or asthma.