Calcium, sodium, potassium, and magnesium ions after translocation through ion channels or by transport proteins can cause activation of release processes, contractile proteins, adenylate and guanylate cyclase, phosphodiesterases, protein kinases, phospholipases, ATPases and other enzymes. Receptors of various types and various toxins serve to modulate ion channels and generation of second messengers including cyclic nucleotides, diacylglycerides, arachidonic acid and phosphatidic acid. Modulatory interactions or """"""""cross-talk"""""""" occurs both between the second messenger systems and with the ion transport systems. Maitotoxin, a marine polyether increases phospholipid, leading to inositol phosphate and diacyclglyceride production. The primary site of action of maitotoxin appears to be a calcium channel similar in sensitivity to blockade by organic compounds to the so-called receptor- operated calcium (ROC) channels. The efficacy of blockade of maitotoxin-elicited calcium flux in fibroblasts by a variety of organic calcium channel blockers, including the antimitotic imidazoles (miconazole, econazole, etc) proposed as ROC channel blockers, does not correlate with anti-mitotic activity of the blockers in fibroblasts. The most potent blockers for maitotoxin-elicited calcium flux were certain of the imidazoles, R-verapamil and amiloride analogs containing a benzyl substituent on the amidine moiety. Pheochromocytoma cells appear to contain both an ATP and a UTP receptor, both of which lead to an increase in influx of calcium and generation of inositol phosphate. ATP and ATP analogues but not UTP triggers the following sequelae: A sustained elevation of intracellular calcium presumably through ROC channels. Release of norepinephrine. Activation of calcium-dependent potassium channels.
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