Cyclic nucleotide phosphodiesterase activity, role

The role of cyclic AMP as modulator of prolactin secretion was first suggested by the finding of a stimulatory effect of cyclic AMP derivatives (17-22) and inhibitors of cyclic nucleotide phosphodiesterase activity such as theophylline and IBMX (22-26) on the secretion of this hormone. More convincing evidence supporting a role of cyclic AMP in the action of dopamine on prolactin secretion had to be obtained, however, by measurement of adenohypophysial adenylate cyclase activity or cyclic AMP accumulation under the influence of the catecholamine. As illustrated in Fig. 1, addition of 100 nM dopamine to male rat hemipituitaries led to a rapid inhibition of cyclic AMP accumulation, a maximal effect (30% inhibition) being already obtained 5 min after addition of the catecholamine. Thus, while dopamine is well known to stimulate adenylate cyclase activity in the striatum (27, 28), its effect at the adenohypophysial level in intact cells is inhibitory. Dopamine has also been found to exert parallel inhibitory effects on cyclic AMP levels and prolactin release in ovine adenohypophysial cells in culture (29) and purified rat mammotrophs (30). Using paired hemipituitaries obtained from female rats, Ray and Wallis (22) have found a rapid inhibitory effect of dopamine on cyclic AMP accumulation to approximately 75% of control. 

Dopamine activates adenylate cyclase and phospholipase C (PLC) via a D, receptor and inhibits through a D2 receptor, thereby regulating the production of intracellular second messengers, cAMP, Ca2+, and 1,2-diacylglycerol. D, and D2 receptors are decreased in the striatum of patients with dementia. There is considerable evidence to suggest that intracellular levels of cAMP have a protective role for dopaminergic neurons. Intracellular concentrations of cyclic nucleotides are regulated by cyclic nucleotide phosphodiesterases and CaMPDE, one of the most intensely studied and best-characterized phosphodiesterases. 

The above-described data show that CRF added to cells of the rat Intermediate lobe In culture causes a rapid stimulation of oe-MSH release and cyclic AMP accumulation, thus demonstrating a direct action of the peptide on pars intermedia cells (15). It is however difficult, using intact cells, to dissociate between increases in cyclic AMP levels due to stimulation of adenylate cyclase activity or to Inhibition of cyclic nucleotide phosphodiesterase or to a combination of both effects. Definitive proof of the role of adenylate cyclase In the action of CRF In the intermediate lobe of the pituitary gland is provided by the following findings of a CRF-lnduced stimulation of adenylate cyclase activity in homogenate of rat and bovine pars Intermedia cells. 

The regulatory role of calcium ions in intermediary metabolism is well documented. Calcium has been shown to be involved in activation or inhibition of specific enzyme systems [105], For example, it activates cyclic nucleotide phosphodiesterase, phosphofructokinase, fructose 1 6 biphosphatase, glycerol phosphate dehydrogenase, pyruvate dehydrogenase phosphatase and pyruvate dehydrogenase kinase. Calcium ions inhibit pyruvate kinase, pyruvate carboxylase, Na+/K+-AT-Pase and adenylate cyclase. 

The role of drugs interacting at GPCRs as agonists is to accelerate the exchange of GDP for GTP on the a subunits of these G proteins. Once activated by a-GTP, AC remains activated until (Vj hydrolyzes the bound GTP to GDP, which returns the system to its ground state. A single AC activation produces many molecules of cyclic AMP, which, in turn, can activate PKA. Cyclic AMP is eliminated by a combination of hydrolysis, catalyzed by cyclic nucleotide phosphodiesterases, and extrusion by several plasma membrane transport proteins. 

More recently, Bentrude has studied the chair-twist conformational interconversion for the phosphate ring of cyclic nucleotides, which he has shown to have a low energy barrier. This has prompted him to propose a role for conformational interconversion in the activation of protein kinases (and indeed in the mechanism of phosphodiesterase-catalysed hydrolysis) (Nelson et al.. 1987 Beres ei al.. 1987). It is speculated that strong coordination of... 

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