Physiological functions are mediated in different cells by a variety of second messengers, including cyclic AMP and cyclic GMP. Ions such as calcium, sodium and magnesium can serve after translocation through ion channels or by transport proteins as second messengers to cause activation of release processes, contractile proteins, adenylate and guanylate cyclase, phosphodiesterases, protein kinases, phospholipases, ATPases and other enzymes. Enzymatic hydrolysis of phospholipids can also generate second messengers, such as arachidonate, which serves as a precursor of prostanoids, diacylglycerides, which serve as activators of protein kinsse C, and inositol phosphates, which serve as mobilizers of internal calcium ions. Receptors of various types serve to modulate ion channels and generation of second messengers. Adenosine stimulates cyclic AMP formation through an A2 receptor and inhibits cyclic AMP formation through an A1 receptor and also can regulate calcium and potassium channels and phosphoinositide breakdown. Maitotoxin (MTX), a high molecular weight polyether toxin, is a very potent stimulant of phosphoinositide breakdown in a wide range of cell types. This effect occurs at lower concentrations of MTX than those required to activate calcium channels. Blockade of calcium channels has no effect on MTX-evoked stimulation of phosphoinositide breakdown. But removal of extracellular calcium completely blocks MTX-induced effects. MTX-induced phosphoinositide breakdown has similar effects to phorbol esters on translocation of protein kinase C and on responsiveness of cyclic AMP-systems in two cell lines. Further selective xanthine antagonists for adenosine receptors were developed with 8-cyclohexyl-1,3-dipropylxanthine being 130-fold selective for A1 receptors and 8-cyclohexylcaffeine being 150-fold selective for A2 receptors. Certain 9-phenyl-7-deazaadenines and hypoxanthines are potent adenosine antagonists.
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