Calmodulin Sodium-calcium

Sodium and potassium are not the only ions which can participate in pumps and channels. Calcium is also pumped, channeled, exhanged,and stored. See Figure 23. Calcium concentration within the cell cytoplasm is very low. This allows the calcium to play a pivotal role in cellular activity. The cytoplasmic protein calmodulin binds and stores calcium ion. Various intracellular structures and organelles such as the mitochondria and sarcoplasmic reticulum also store calcium. Calcium is vital to such functions as the release of neurotransmitters from nerve cells. There are at least seven known modes of biochemical action for this ion, one of the most important of which involves stimulation of cardiac muscle protein (actin-myosin). Certain types of angina (heart pain) are believed to be caused by abnormal stimulation of cardiac arteries and muscle (coronary spasm) A relatively new class of drugs, known as the calcium channel blockers, has brought relief from pain and arrhythmias (irregular heart beats). 

In cell culture preparations, diphenylhydantoin, carbamazepine and valproate have been shown to reduce membrane excitability at therapeutically relevant concentrations. This membrane-stabilizing effect is probably due to a block in the sodium channels. High concentrations of diazepam also have similar effects, and the membrane-stabilizing action correlates with the action of these anticonvulsants in inhibiting maximal electroshock seizures. Intracellular studies have shown that, in synaptosomes, most anticonvulsants inhibit calcium-dependent calmodulin protein kinase, an effect which would contribute to a reduction in neurotransmitter release. This action of anticonvulsants would appear to correlate with the potency of the drugs in inhibiting electroshock seizures. The result of all these disparate actions of anticonvulsants would be to diminish synaptic efficacy and thereby reduce seizure spread from an epileptic focus. 

In the presence of 10 24 mM sodium caprate on Caco-2 monolayers a dilatation of the tight junctions was observed (Anderberg et al. 1993). Based on Caco-2 studies Tomita et al. (1995) and Lindmark et al. (1998) proposed the activation of phospholipase C, followed by an increase in inositol triphosphate and intracellular calcium concentration leading to a contraction of calmodulin-dependent... 

Figure 6.1. Overview of cellular calcium transport. Calcium enters the cell through voltage- or ligand-gated channels (left). It is extmded by ATP-driven pumps or by sodium antiport (right). Both the mitochondria and the endoplasmic reticulum serve as intracellular calcium stores. The cytosolic concentration is kept at -100 nM under resting conditions. CaM Calmodulin.

Mitochondrial dysfunction is believed to play a vital role in the pathogenesis of acute renal failure. In the face of inadequate production of mitochondrial ATP, sodium and calcium efflux from the cell, which requires ATP, is curtailed. This leads to the swelling of the cell and activation of the calcium-calmodulin complex. The latter may activate phospholipases, which in turn can damage the cell membrane and cause swelling of the cell, leading to its death. The cell debris serves as a substrate for tubular obstruction and supports the maintenance phase of acute renal failure. Complications of casts solidifying in the tubular lumen can be avoided by early measures to prevent cell death. 

Figure 7.1. Diagrammatic representation of cellular Ca2 movements. Calcium ions (Ca2 ) may cross the sarcolemma by the following routes (7) voltage-operated calcium channels Q) receptor-operated calcium channels ( ) fast sodium channels (7) Ca2 -A TPase pump (J) Na -Ca2 exchange and Ca2 + leak pathways. Inside the cell, Ca2 may be taken up into and released from mitochondria (MIT) and sarcoplasmic reticulum (SR) (8). Ca2 also binds to the intracellular proteins, calmodulin and troponin C. REC represents a specific membrane receptor site.

Shackelford, D. A., and Zivin, J. A. (1993) Renaturation of calcium/calmodulin-dependent protein kinase activity after electrophoretic transfer from sodium dodecyl sulfate-poly-acrylamide gels to membranes. Anal. Biochem. 211, 131-138. 

Joseph and Meltzer (1909) established that the toxicity of the alkaline earth metals (magnesium, calcium, potassium, and sodium) to dogs was in inverse proportion to the amounts in the dog s serum. Cox and Harrison (1983) compared Williams et al. (1982) mouse LDjq cation toxicity valnes with the cation s ability to mimic Ca + in stimulating the intracellular Ca + receptor protein, calmodulin. Williams et al. 

Although the active transport of riboflavin across the gut wall and across other cell membrane barriers within the animal is a saturable process, if large pharmacological amounts are present then the slower and less efficient but nonsaturable process of passive absorption predominates and contributes significantly to the total mass transfer. The active transport process is increased in riboflavin deficiency and decreased if the riboflavin content of the tissues is high. The transport pathway involves calcium and calmodulin but not sodium. Specific riboflavin receptors have recently been identified, as has a role for microtubules in transport. 

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