Cyclic nucleotides calcium effects

Before discussing effects of the retinoids on the cyclic nucleotide/calcium-dependent regulatory systems, it is necessary to identify the various components of these systems. The cyclic nucleotide system contains many elements (1) the substrate ATP (or GTP) (2) the synthetic and degradative enzymes adenylate or... 

There are several mechanisms involved in the vasodilator effect of flavonoids. The main mechanism seems to be related to the inhibition of protein kinase C or some of the processes activated by this protein. The inhibition of other protein kinases and cyclic nucleotide phosphodiesterase activity and blockage of calcium entry can also contribute to this effect to a greater or lesser extent (Alvarez Castro and Orallo, 2003 Herrera and others 1996). Certain flavonoids, like the flavonol myricetin, have a two-phase action on blood vessels vasoconstrictor in lowest active concentrations and vasodilator in higher concentrations (Alvarez Castro and Orallo, 2003). 

While ionophore-stimulated 5-LO product release from neutrophils is often used as an indication of 5-LO inhibition, one must interpret these results cautiously. For example, halothane, an inhalation anaesthetic which may cause membrane perturbation [26], and colchicine, a microtubule disrupter [27], both were active, but presumably not because of 5-LO inhibition. A23187 is assumed to stimulate 5-LO by raising the intracellular calcium level, but this agent causes many other effects which may or may not be related to 5-LO activation, including changes in membrane potential, protein phosphorylation, phospholipid turnover, cyclic nucleotide levels, and DNA and protein synthesis [28]. Also, the effects of some putative 5-LO inhibitors on product release from neutrophils has been shown to vary with the stimulant used [29]. 

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. 

E. F. Du Toit, C. A. Muller, J. McCarthy, L. H. Opie, Levosimendan effects of a calcium sensitizer on function and arrhythmias and cyclic nucleotide levels during ischemia/reperfusion in the Langcndorff-perfused guinea pig heart, J Pharmacol Exp Ther 290, 505-14 (1999). 

Cyclic AMP is catabolized to 5 -adenosine monophosphate by the enzyme cyclic nucleotide phosphodiesterase, which terminates any further cAMP-initiated reactions. This enzyme also requires Mg + for activity. Calcium, again in consort with calmodulin, can stimulate phosphodiesterase activity. Phosphodiesterase appears to exist in multiple forms, each with specificity toward different substrates. Calcium and calmodulin activate only one form of the enzyme. The enzyme is potently inhibited by methyl xanthines, such as caffeine, theophylline, and theobromine. It is believed that at least part of the pharmacological effects of such compounds can be explained through their inhibition of phosphodiesterase and the consequent reduction in the catabolism of cAMP. 

The frequency and amplitude of calcium sparks are modulated by SR calcium load, protein kinase C (PKC) and cyclic nucleotides/cyclic nucleotide-dependent protein kinases (Bonev et al. 1997 Porter et al. 1997). Calcium spark frequency decreases following activation of PKC (Bonev et al. 1997). This effect appears to be mediated by a direct action of PKC on... 

GU-7, a 3-arylcoumarin derivative, has been isolated fi om Glycyrrhizae radix, which is a crude herbal medicine. GU-7 caused inhibition of platelet aggregation, phosphorylation of 40K and 20K dalton proteins, inositol 1,4,5-trisphosphate production, intraplatelet calcium increase and phosphodiesterase activity in vitro. The data indicate that GU-7 inhibits platelet aggregation by increasing intraplatelet cAMP concentration. Antiplatelet action may also explain the mechanism by which traditional medicines are effective in diabetic neuropathy [236]. Osthole causes hypotension in vivo, and inhibits platelet aggregation and smooth muscle contraction in vitro. It may interfere with calcium influx and cyclic nucleotide phosphodiesterases [12]. Cloricromene, a synthetic coumarin derivative, also possesses antithrombotic-antiplatelet activity [237]. Some of these properties of cloricromene have been attributed to the inhibition of arachidonate release from membrane phospholipids [12]. 

There are 11 different PDE families (PDEl-11) with different substrate specificity, affinity, sensitivity to inhibitors, and tissue localization. In addition, there are exonucleases such as 5 -nucleotide phosphodiesterase (PDE 1) and 3 -nucleotide phosphodiesterase (PDE 11) that hydrolyze phosphodi-ester bounds. These enzymes have several known functions in nucleic acids. By using all these enzymes in a sensor surface and by measuring changes in fluorescence polarization it was concluded that YTX binds to cyclic nucleotide PDEl, with a calcium-dependent effect, PDE3, and PDE4, and shows high affinity by exonuclease PDE 1 [15,16]. 

Calmodulin, an intracellular calcium-combining protein, is involved in many bodily processes such as secretion, activation of myosin kinase, and cyclic nucleotide metabolism. A similar protein, troponin-r, regulates conformational changes in skeletal muscle. The control of skeletal muscle contraction depends entirely on intracellular calcium. Hence those drugs such as nifedepine (Section 14.2) which block calcium channels, have no effect. On the other hand, smooth and cardiac muscles are much influenced by external calcium levels. 

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. 

A heat-labile inhibitor of CDR has been partially purified from bovine brain. This inhibitor, called modulator binding protein, combines with CDR, thereby causing an inhibition of phosphodiesterase activation (Wang and Desai, 1977). A different inhibitor of CDR has also been found in bovine brain. This inhibitor is heat-stable, has a molecular weight of about 70,000, and counteracts the stimulation of cyclic nucleotide phosphodiesterase by CDR (Sharma et al., 1978). This heat-stable inhibitor has no effect on calcium or CDR-independent cyclic nucleotide phosphodiesterase. The exact physiological significance of this inhibitor is unknown. 

Many other receptors are 7-helix transmembrane proteins, which activate guanine nucleotide G proteins (Chapter 11, Section D, 3). The G proteins couple some receptors directly to Ca2+ channels they couple other receptors to adenylate cyclase and cyclic AMP-activated channels and yet others via phospholipase C to K+ channels and indirectly to Ca2+ channels (Fig. 30-19). All of these G protein coupled receptors are referred to as metabotropic receptors. A single synapse often contains both ionotropic receptors and metabotropic receptors. The ionotropic receptors induce a rapid (< 1 ms) response, while the metabotropic receptors act more slowly. However, in most cases the final effect is the release of calcium ions into the cytoplasm... 

---