CROSS-TALK BETWEEN CYCLIC-AMP AND THE POLYPHOSPHOINOSITIDE SIGNALING CASCADE IN IRIS SPHINCTER AND OTHER NONVASCULAR SMOOTH-MUSCLE

Nonvascular smooth muscle, such as the iris sphincter, receives double reciprocal innervation: stimulation of the parasympathetic nervous sy stem (cholinergic muscarinic), which functions through the polyphospho inositide (PPI) signaling pathway, contracts it, while activation of t he sympathetic nervous system (beta-adrenergic), which functions throu gh the cAMP system, relaxes it. Interactions between the two second me ssenger systems are important in regulation of smooth muscle tone and represent an important focal point for pharmacological manipulation. H ere, I have summarized the experimental evidence in support of the hyp othesis that the cross talk between cAMP and the PPI cascade could con stitute a biochemical correlate for this functional antagonism. Recent studies suggest that cAMP inhibition is on Ca2+ mobilization rather t han myosin light chain phosphorylation. Thus, cAMP-elevating agents, w hich inhibit agonist-induced PPI hydrolysis, are effective relaxants. Furthermore, inositol 1,4,5-trisphosphate (IP3) appears to be involved in both Ca2+ release from the sarcoplasmic reticulum and in Ca2+ infl ux through the plasma membrane, and since a reduction in intracellular Ca2+ ([Ca2+](i)) is the underlying mechanism for cAMP-mediated relaxa tion, an important target for cAMP inhibition would be either to inhib it IP3 production or to stimulate IP3 inactivation. In the iris sphinc ter and other nonvascular smooth muscle there is reasonable experiment al evidence that shows that cAMP inhibits phospholipase C activation a nd stimulates IP3 3-kinase activity, both of which can result in: (i) reduction in IP3, concentrations and (ii) reduction in IP3-dependent C a2+ mobilization, which may lead to muscle relaxation. In addition to IP3-induced Ca2+ mobilization, changes in [Ca2+](i) are the result of the interplay of many processes which may also serve as potential site s for cAMP inhibition. A great deal of progress has been made on the c ross talk between cAMP and the PPI signaling cascade in the past decad e, and there will be more made on the regulation of the second messeng er systems and their involvement in smooth muscle tone in the coming y ears. Clearly, an understanding of the physiological and pathophysiolo gical regulation of smooth muscle tone is central to the development o f novel therapeutic agents for the treatment of diseases such as asthm a and glaucoma, where cAMP-elevating drugs are currently employed.