Calcium flux mechanisms

The mechanism of action of the vitamin D metabolites remains under active investigation. However, calcitriol is well established as the most potent agent with respect to stimulation of intestinal calcium and phosphate transport and bone resorption. Calcitriol appears to act on the intestine both by induction of new protein synthesis (eg, calcium-binding protein and TRPV6, an intestinal calcium channel) and by modulation of calcium flux across the brush border and basolateral membranes by a means that does not require new protein synthesis. The molecular action of calcitriol on bone has received less attention. However, like PTH, calcitriol can induce RANK ligand in osteoblasts and proteins such as osteocalcin, which may regulate the mineralization process. The metabolites 25(OH)D and 24,25(OH)2D are far less... 

The use of new transcriptome information for discovery of novel drug candidates is desirable, as the control of schistosomiasis relies mostly on the use of a single drug, praziquantel, a heterocyclic pyrazino-isoquinolone. This drug exerts multiple effects, such as damage to the tegumental membrane, changes in calcium flux and muscular contractions in the parasite by a mechanism or mechanisms that are not... 

Rodriguez-Moreno A, Lopez-Garcia JC, Lerma J (2000) Two populations of kainate receptors with separate signaling mechanisms in hippocampal intemeurons. PNAS 97 1293-8 Rodriguez-Moreno A, Sihra TS (2004) Presynaptic kainate receptor facilitation of glutamate release involves protein kinase A in the rat hippocampus. J Physiol (Lond) 557 733—45 Rogers M, Dani JA (1995) Comparison of quantitative calcium flux through NMDA, ATP, and ACh receptor channels. Biophys J 68 501-6... 

The close alignment of cytoplasmic and ER membranes is, in fact, cmcially important for the workings of excitation-contraction coupling in the skeletal muscle. In these cells, we have a unique mechanism of activation of one channel by another The RyR is directly hooked up to a cytosolic loop of the dihydropyridine receptor (DHPR Figure 6.6a, b). Membrane depolarization will cause a conformational change to the DHPR, which in turn is directly and mechanically transmitted to the RyR, so that both channels open synchronously. This even works in the absence of any calcium flux across the cytoplasmic membrane - experimentally, skeletal muscle cells can be induced to contract in calcium-free buffers. 

Studies by Scmtton et. al. and Stormoiken and his associates, have shown compromised functional response to epinephrine in apparently normal individuals (52,53). Weiss et. al. have described secretion defects from patients with bleeding disorders (54). White et. al. have followed functional response of platelets of patients with diabetes and Hermasky-Pudlak Syndrome (HPS) whose platelets lack dense bodies. Platelets of patients with HPS exhibit compromised response to the action of agonists (55). Hardisty et. al., and Ware and associates, have provided further evidence for altered signal transduction mechanisms. These and other studies seem to suggest that an impaired intracellular calcium flux may be the chief cause of platelet dysfunction (56-58, discussed in other chapters). 

Children with nephrotic syndronre were found to have elevated excretion of TXBj, and the TP receptor agonist, STAj, stimulated a greater calcium flux in their platelets than in platelets fiom control subjects or from patients with nephrotic syndome who were in ronission (241). TP receptor binding was not studied, and the mechanism responsible for the accentuated response to STAj was not defined. 

Mayahara T, Kamimura T, Tanaka M, et al. 1982. Modification of calcium fluxes by dimethyl sulfoxide and 2-butoxyethanol in sarcoplasmic reticulum vesicles A possible mechanism for skeletal muscle relaxation induced by dimethyl sulfoxide. Physiol Bohemoslov 31(4) 297-303. 

The xanthine theophylline has been used for several decades in the treatment of asthma. This compound produces different effects at the cellular level, including phosphodiesterase isoenzyme inhibition, adenosine antagonism, catecholamine secretion enhancement, and the modulation of calcium fluxes. Recently, theophylline was found to have both immunomodulatory and anti-inflammatory properties therefore, interest in its use in patients with asthma has been renewed [103]. Recent studies have thus discovered that at low doses, theophylline is able to decrease airway inflammation, accelerate eosinophil apoptosis, and decrease recruitment of lymphocytes and neutrophils to the lungs. Although it is classified as a phosphodiesterase inhibitor, its exact therapeutic mechanism of action remains undetermined [104]. Of the new mechanisms that have been included in the potential mode of action of theophylline, one is the apoptosis of inflammatory cells. In eosinophils and lymphocytes, for example, this effect is due to the compound s ability to inhibit phosphodiesterase, which leads to an even more pronounced increase in intracellular cAMP levels than that which occurs when adenylate cyclase, the enzyme that synthesizes cAMP, is activated. This inhibition and the resulting cAMP level increase thus lead to... 

Regulation of Calcium Homeostasis Calcium homeostasis necessitates the maintenance of a dynamic equilibrium of calcium fluxes between three different compartments which harbor the mineral ion in vastly different concentrations. Thus, homeostatic control mechanisms ought to modulate calcium fluxes between different body compartments in a way which allows the generation and maintenance of steep concentration gradients between the skeletal tissue, the extracellular fluid and the intracellular - that is, the cytoplasmic compartment. Of particular importance thereby is the rigid control of plasma free Ca " ", because even small deviations from the normal level induce profound changes in both intracellular free Ca, as well as in the amount of calcium deposited at skeletal sites, inevitably causing adverse effects on bone health (cf. Whedon 1980). 

Diazoxide increases blood glucose concentration (diazoxide-induced hyperglycemia) by several different mechanisms by inhibiting pancreatic insulin secretion, by stimulating release of catecholamines, or by increasing hepatic release of glucose (6,9). The precise mechanism of inhibition of insulin release has not been elucidated but, possibly, may result from an effect of diazoxide on cell-membrane potassium channels and calcium flux. 

In rat brain slices and in cerebeller granule neurons in culture, endocannabinoids were shown to modulate calcium flux through NMDA chaimels (Hampson et al,1998 Netzeband et al., 1999). In rat brain slices, AEA inhibited calcium influx brought about by addition of NMDA (Hampson et al., 1998). In this model, addition of NMDA alone caused an increase in intracellular calcium. The proposed mechanism responsible for the endocannabinoid effect was an opposing inhibition of calcium entry into the cells brought about by CB,-receptor inhibition of voltage-dependent P/Q-type calcium channels. 

Arachidonic acid, TXA2, PGH2 and their stable mimetics produce an increase in intracellular free calcium in human platelets or alter the binding or flux of calcium in platelet membrane vesicles " ". These effects were blocked by the receptor antagonist, 13-azaprostanoic acid ". The dense tubular system is believed to be the source of calcium. The mechanism by which calcium is elevated in platelets by TXA2/PGH2 or their mimetics remains unknown. However, much recent evidence suggests that turnover of phophatidyl inositol polyphosphates plays an important intermediary role ". ... 

I believe that the clinical practice of medicine and cardiology of the future will be influenced more, much more, profoundly by studies of human genetics, molecular biology, cellular physiology and experimental pathology, by studies of problems such as the mechanisms of endocytosis as the mechanisms of on-docystosis, the control of calcium fluxes across the sarcolemma of the colemma of the myocardium and specialised cardiac tissue, the fundamental mechanisms by which platelets adhere to the arterial endothelium or by which adrenalin acts on its receptors and vascular smooth muscle the renal cortex and other tissues by all these, and other fundamental studies. It is becoming even clearer that in most... 

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