Receptors agonists and various toxins serve to modulate ion channels and generation of second messengers, including cyclic nucleotides, inositol phosphates diacylglycerides, arachidonic acid prostaglandins, sphingosine, and phosphatidic acid. 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. Modulatory interactions or """"""""cross-talk"""""""" occurs both between the second messenger systems and the ion transport systems. Maitotoxin-from a marine dinoflagellate activates unique, calcium channels, which do not appear to be identical to any know calcium-channel, including the so-called calcium release-activated calcium (CRAC) channel. However, both maitotoxin and CRAC channels are effectively blocked by certain imidazoles (SKF 96365, miconazole, clotrimazole). Both channels are also blocked by trifluoperazine, but there are many other agents that block only the maitotoxin-activated channel. Loperamide is one of the most potent blockers of maitotoxin-elicited channels, but causes an apparent enhancement of calcium influx through the CRAC-channels that have been opened as a result of receptor-, thapsigargin-, or ionomycin-elicited depletion of IP3-sensitive intracellular pools of calcium in a variety of cell types. The effect of loperamide is unique, highly dependent on structure, and not readily reversed by imidazoles. Loperamide does not have any effect on levels of intracellular calcium if CRAC channels have not been activated. Loperamide does not augment sphingosine-elicited influx of calcium. Thus, loperamide does not augment sphingosine-elicited influx of calcium nor does augment influx of calcium through L-type calcium channels. The imidazoles, in addition to blocking CRAC channels, cause both release and influx of calcium in HL60 cells. Calmidazolium causes the greatest influx, but simpler analogs of calmidazolium have no effect. Erythrina alkaloids cause both competitive and noncompetitive blockade of nicotinic channels. Erysovine is the most potent member of these alkaloids at the central neuronal nicotinic receptor-channel. Tropane analogs of epiboxidine had nanomolar affinities for central nicotinic receptor-channels. Remarkably an N-benzyl derivative retained agonist activity. From a series of tropanes related in structure to a Chinese herbal alkaloid baogongteng A, the analog 6beta-acetoxytropane proved to be a potent muscarinic agonist with some selectivity towards M2-receptors. Other analogs appeared to be selective towards M1-receptors and, therefore, may have potential in decreasing cognitive deficits.
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