Effects on intracellular calcium

Early studies reported the lack of stimulation of PLC activity by D2 agonist in the striatum but the measures were taken in striatal slices in which D2 agonists could have very complex effects (Kelly et al., 1988 Pizzi et al., 1988 Rubinstein and Hitzemann, 1990). Mobilization of Ca2+ from intracellular stores by D2 receptor activation has been observed in striatal medium spiny neurons (Hernandez-Lopez et al., 2000). The medium spiny neurons express PLCpl and the D2 receptor activation could stimulate this enzyme by mobilizing Gpy subunits (Hernandez-Lopez et al., 2000). The elevation of intracellular Ca2+ in medium spiny neurons was very transient, since it promoted an immediate closure of L type-Ca2+ channels, due to the activation of the Ca2+-dependent protein phosphatase, calcineurin and subsequent dephosphorylation of the L-type Ca2+ channels (Hernandez-Lopez et al., 2000). 

Several studies have revealed that the D2 receptors modulate the state of phosphorylation of DARPP-32. In mouse striatal slices, the D2 agonist quinpirole decreased the basal phosphorylation of DARPP-32 on Thr-34, and antagonized the phosphorylation produced by the application of D1 agonist, forskolin or 8-bromo-cAMP (Nishi et al., 1997). This D2 effect was calcium-dependent and was blocked by cyclosporine A, an inhibitor of calcineurin, suggesting that it involved an increase in intracellular Ca2+ and a dephosphorylation of DARPP-32 by calcineurin. This study showed that an activation of 

D1 and D2 receptors in the striatum exerts opposite effects on the state of phosphorylation of DARPP-32. Studies carried out in vivo have confirmed the importance of D2 receptors in regulating the state of phosphorylation of DARPP-32 since treatments with the D2 antagonist eticlopride produced an increase in the phosphorylation of DARPP-32 on Thr-34 (Svenningsson et ah, 2000). This effect depended on a tonic activation of the cAMP pathway via D1 receptor or A2 receptor. In addition, in yeast, two-hybrid analysis has shown that spinophilin, but not the closely related protein neurabin, binds to the third intracellular loop of D2 receptors (Smith et al., 1999). This provides a possible link between D2 receptor and PP-1, the major target of Thr-34 phosphorylated DARPP-32, since spinophilin interacts with PP-1 (as mentioned earlier). 

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Subsequently, several studies have provided more detailed information on domoic acid action as an excitotoxin. The presynaptic action of domoic acid to induce glutamate release was extended to include other excitatoiy and inhibitoiy neurotransmitters and linked to the entiy of calcium through voltage operated calcium channels, suggesting that domoic acid toxicity may involve multiple transmitters (Brown and Nijjar 1995 Duran et al. 1995a Malva et al. 1996). Domoic acid effects on intracellular calcium were next characterized by FURA-2 imaging of the hilar region of individual... 

Mode of action. Caffeine and theophylline have complex and incompletely elucidated actions, which include inhibition of phosphodiesterase (the enzyme that breaks down cyclic AMP, see p. 191), effects on intracellular calcium distribution, and noradrenergic function. When theophylline (as aminophylline) is used alongside salbutamol in asthma its action adds up to increased benefit to the bronchi, but increased risk to the heart. 

Farghali, H., Kamenikowa, L., Hynle, S., Kmonlckova, E. Silymarin effects on intracellular calcium and cytotoxicity a study in perfused rat hepatocytes after oxidative stress injury. Pharm. Res. 2000 41 231-237... 

Covalent binding of reactive metabolites Effect on intracellular calcium... 

Because of its powerful vasoconstrictor properties and its effects on intracellular calcium, ET-1 has been implicated in the pathogenesis of hypertension, coronary vasospasm, and heart failure. A number of studies suggest a role for ET-1 in puimonary hypertension as well as in systemic hypertension. Additionally, ET-1 has been shown to be released by the failing myocardium, where it can contribute to cardiac calcium overload and hypertrophy. 

Larsson, D., Nemere, L, Sundell, K. 2001. Putative basal lateral membrane receptors for 24,25-dihydroxyvitamin D(3) in carp and Atlantic cod enterocytes Characterization of binding and effects on intracellular calcium regulation. J. Cell Biochem. 83(2) 171-86. 

Melittins are peptides of 26 amino acids found in Apis venoms (119, 120). Melittin comprises about 40% to 50% of the dry weight of Apis mellifera venom. At moderate and high concentrations, it exists primarily in the form of tetramers (120, 121), which can be immunogenic and allergenic (123). Tetrameric melittin is a potent lytic agent for cells and can also function as an ion channel (124, 125, 126). Melittin has profound effects on intracellular calcium and interacts with calmodulin (127, 128, 129). It is an amphiphilic and amphipathic molecule that has been found to be very useful in studies of cell lysis, membrane function, calcium regulation and as a model for proteins and peptides. Natural and synthetic melittin have been used in over a 1000 published studies in many areas of science. 

Pretreatment of rats with difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, prior to exposure to a tremorigenic dose of chlordecone, also resulted in inhibition of the tremor (Tilson et al. 1986b). DFMO was more effective if given 5 hours prior to the chlordecone than if given 24 hours prior to exposure. The DFMO was ineffective if given 19 hours after chlordecone exposure. These results suggest an interaction of the polyamine synthetic pathway with tremors produced by chlordecone. The mechanism of the interaction is unclear but may involve effects of polyamines on intracellular calcium homeostasis. Persons being treated with DFMO for cancer or protozoal infections would be likely to have reduced tremor severity after exposure to chlordecone. 

The occurrence and timing of effects on intracellular ionized calcium concentration, lysosomal mass, oxidative stress or plasma membrane permeability frequently provide additional information indicative of mechanism of toxicity (Table 14.5). 

Sawyer, T.W., Hamilton, M.G. (2000). Effect of intracellular calcium modulation on sulfur mustard cytotoxicity in cultured human neonatal keratinocytes. Toxicol. In Vitro 14 149-57. 

Sabra R and Branch RA. Effect of amphotericin B on intracellular calcium levels in cultured glomerular mesangial cells. Eur ] Pharmacol 226 79-85,1992. 

Elsin YEI, Cheng CEI,Tzen JT, Wu MJ, Shu KEI, Chen EIC. Effect of aristolochic acid on intracellular calcium concentration and its links with apoptosis in renal tubular cells. Apoptosis 2006 11 2167-2177... 

Effects Hypoxia/Reoxygenation on Intracellular Calcium Ion Homeostasis in Ventricular Myocytes during Halothane Exposure Paui R. Knight, Mitchell D. Smith, and Bruce A. Davidson... 

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. 

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