Phosphodiesterases phosphorylation

T. Rahn, L. Ronnstrand, C. Wern-STEDT, M.-J. Leroy, H. Tornqvist, V. Manganiello, P. Belerage, and E. De-GERMAN, Identification of the site in the cGMP-inhibited phosphodiesterase phosphorylated in adipocytes in response to insulin and isoproterenol, J. Biol. Chem., 1996, 277, 11575-11580. 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

When glucagon levels fall, cAMP phosphodiesterase destroys the accumulated cAMP, and specific protein phosphatases remove the phosphate from the phosphoproteins. These phosphatases themselves are often regulated by phosphorylation—yes, there are phosphatase kinases and phosphatase phosphatases. It s really easy to lose it here, but the key factor is that increased glucagon levels lead to increased protein phosphorylation, and decreased glucagon levels lead to decreased protein phosphorylation. 

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. 

One of the primary mechanisms for regulation of phosphodiesterase enzyme activity is phosphorylation 374 Phosphodiesterase inhibitors show promise as pharmacotherapeutic agents 374... 

FIGURE 21-6 Schematic illustration of the overall structure and regulatory sites of eleven different phosphodiesterase subtypes. The catalytic domain of the phosphodiesterases are relatively conserved, and the preferred substrate(s) for each type is shown. The regulatory domains are more variable and contain the sites for binding of Ca2+/calmodulin (CaM) and cGMP, as well as GAF and PAS domains. The regulatory domains also contain sites of phosphorylation by cAMP-dependent protein kinase (PKA). 

One of the primary mechanisms for regulation of phosphodiesterase enzyme activity is phosphorylation. 

FIGURE 50-5 A model for the transduction of odors in OSNs. The individual steps are detailed in the text. Note that several feedback loops modulate the odor response, including inhibition of the CNG channel by Ca2+ ions (purple balls) that permeate the channel, and a Ca2+/calmodulin (CaM) -mediated desensitization of the channel that underlies rapid odor adaptation. Several other mechanisms, including phosphodiesterase-mediated hydrolysis of the second messenger, cAMP, and phosphorylation of the OR by various kinases, have also been described. 

Phosphorylation of cardiac calcium-channel proteins increases the probability of channel opening during membrane depolarization. It should be noted that cAMP is inactivated by phosphodiesterase. Inhibitors of this enzyme elevate intracellular cAMP concentration and elicit effects resembling those of epinephrine. 

The actions of cAMP are terminated by phosphodiesterases (PDEs) that catalyze the breakdown of cAMP to 5 -AMP (Diunan and Nestler 1999). There are at least 11 different forms of PDEs that are characterized based on their affinity and selectivity for cAMP, as well as cGMP. In addition, the PDEs are differentially regulated by the cyclic nucleotides themselves, by phosphorylation, and by increased expression of certain splice variants (e.g., some isoforms are... 

---