Calcium, intracellular

Stimulation of the neuron lea ding to electrical activation of the nerve terminal in a physiologically relevant manner should eUcit a calcium-dependent release of the neurotransmitter. Although release is dependent on extracellular calcium, intracellular calcium homeostasis may also modulate the process. Neurotransmitter release that is independent of extracellular calcium is usually artifactual, or in some cases may represent release from a non-neuronal sources such as gha (3). 

Another mechanism in initiating the contraction is agonist-induced contraction. It results from the hydrolysis of membrane phosphatidylinositol and the formation of inositol triphosphate (IP3)- IP3 in turn triggers the release of intracellular calcium from the sarcoplasmic reticulum and the influx of more extracellular calcium. The third mechanism in triggering the smooth muscle contraction is the increase of calcium influx through the receptor-operated channels. The increased cytosolic calcium enhances the binding to the protein, calmodulin [73298-54-1]. 

Calcium channel blockers reduce arterial blood pressure by decreasing calcium influx, resulting in a decrease in intracellular calcium (236,237). The arterial smooth muscle tone decreases, thereby decreasing total peripheral resistance. The increase in vascular resistance in hypertension is found to depend much on calcium influx. Calcium channel blockers reduce blood pressure at rest and during exercise. They decrease the transmembranous calcium influx or entry that lead to a net decrease of intracellular calcium and therefore the vascular tone falls, as does blood pressure. 

Diltiazem inhibits calcium influx via voltage-operated channels and therefore decreases intracellular calcium ion. This decreases smooth muscle tone. Diltiazem dilates both large and small arteries and also inhibits a-adrenoceptor activated calcium influx. It differs from verapamil and nifedipine by its use dependence. In order for the blockade to occur, the channels must be in the activated state. Diltiazem has no significant affinity for calmodulin. The side effects are headache, edema, and dizziness. 

Intake of a large amount of sodium chloride negates the antihypertensive effects of diuretics. Other mechanisms, such as direct vasodilating action, decreased responsiveness to vasopressor agents, stimulation of prostacyclin [35121 -78-9] production, and reduction in the intracellular calcium... 

Excitation of smooth muscle via alpha-1 receptors (eg, in the utems, vascular smooth muscle) is accompanied by an increase in intraceUular-free calcium, possibly by stimulation of phosphoUpase C which accelerates the breakdown of polyphosphoinositides to form the second messengers inositol triphosphate (IP3) and diacylglycerol (DAG). IP3 releases intracellular calcium, and DAG, by activation of protein kinase C, may also contribute to signal transduction. In addition, it is also thought that alpha-1 adrenergic receptors may be coupled to another second messenger, a pertussis toxin-sensitive G-protein that mediates the translocation of extracellular calcium. 

The behavior of calcium in the cells can be considered as a metabolic process. There is uptake, distribution, and excretion of calcium in the cells. The uptake of calcium occurs via activation of calcium channels. The end result is elevation of intracellular calcium levels and subsequent activation. Be-... 

Blinks, J. R. (1990). Use of photoproteins as intracellular calcium indicators. Environ. Health Perspect 84 75-81. 

Sheu, Y. A., Kricka, L. J., and Pritchett, D. B. (1993). Measurement of intracellular calcium using bioluminescent aequorin expressed in human cells. Anal. Biochem. 209 343-347. 

Inhibition of the Na+/K+-ATPase leads to a loss of potassium and an increase of sodium within the cell. Secondary intracellular calcium is increased via the Na VCa -exchanger. This results in a positive inotropic effect in the myocardium, with an increase of peak force and a decrease in time to peak tension. Besides this, cardiac glycosides increase vagal activity by effects on the central vagal nuclei, the nodose ganglion and increase in sensitivity of the sinus node to acetylcholine. 

The newest molecular addition to Cl- channels are bestrophins [5]. There are four different bestrophin isoforms in humans. Mutations in Bestl cause Best macular dystrophy, hence their name. All four isoforms induce chloride currents when expressed heterologously. Although they show a dependence on intracellular calcium, their biophysical properties differ from Ca-activated chloride currents typically observed in native cells. Mutagenesis experiments changed the activation of currents and induced slight changes in ion selectivity, lending support to the hypothesis that bestrophins themselves are Cl- channels. 

The ETa receptor activates G proteins of the Gq/n and G12/i3 family. The ETB receptor stimulates G proteins of the G and Gq/11 family. In endothelial cells, activation of the ETB receptor stimulates the release of NO and prostacyclin (PGI2) via pertussis toxin-sensitive G proteins. In smooth muscle cells, the activation of ETA receptors leads to an increase of intracellular calcium via pertussis toxin-insensitive G proteins of the Gq/11 family and to an activation of Rho proteins most likely via G proteins of the Gi2/i3 family. Increase of intracellular calcium results in a calmodulin-dependent activation of the myosin light chain kinase (MLCK, Fig. 2). MLCK phosphorylates the 20 kDa myosin light chain (MLC-20), which then stimulates actin-myosin interaction of vascular smooth muscle cells resulting in vasoconstriction. Since activated Rho... 

Acute over-activation of NHE1 results in a marked elevation in intracellular sodium concentration with a subsequent increase in intracellular calcium, via the Na +/Ca++ exchanger. This in turn triggers a cascade of injurious events that can culminate in tissue dysfunction and ultimately apoptosis and necrosis. This is commonly seen in organs such as the heart, brain and kidneys as a consequence of ischemia-reperfusion. 

NADP can be converted to nicotinic acid adenine dinucleotide phosphate (NAADP), which has distinct functions in the regulation of intracellular calcium stores. The studies of these new roles of NAD(P) in metabolism are in their early stages, but they might soon help to better understand and explain the symptoms of niacin deficiency ( pellagra) [1]. 

Purinergic System. Figure 2 Schematic of sympathetic cotransmission. ATP and NA released from small granular vesicles (SGV) act on P2X and a-i receptors on smooth muscle, respectively. ATP acting on inotropic P2X receptors evokes excitatory junction potentials (EJPs), increase in intracellular calcium ([Ca2+]j) and fast contraction while occupation of metabotropic ar-adrenoceptors leads to production of inositol triphosphate (IP3), increase in [Ca2+]j and slow contraction. Neuropeptide Y (NPY) stored in large granular vesicles (LGV) acts after release both as a prejunctional inhibitory modulator of release of ATP and NA and as a postjunctional modulatory potentiator of the actions of ATP and NA. Soluble nucleotidases are released from nerve varicosities, and are also present as ectonucleotidases. (Reproduced from Burnstock G (2007) Neurotransmission, neuromodulation cotransmission. In Squire LR (ed) New encyclopaedia of neuroscience. Elsevier, The Netherlands (In Press), with permission from Elsevier). 

Wehrens XH, Lehnart SE, Marks AR (2005) Intracellular calcium release and cardiac disease. Annu Rev Physiol 67 69-98... 

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