Cross Talk between Cyclic AMP and the Polyphosphoinositide Signaling Cascade in Iris Sphincter and Other Nonvascular Smooth Muscle

Abstract

Abstract

Nonvascular smooth muscle, such as the iris sphincter, receives double reciprocal innervation: stimulation of the parasympathetic nervous system (cholinergic muscarinic), which functions through the polyphosphoinositide (PPI) signaling pathway, contracts it, while activation of the sympathetic nervous system (β-adrenergic), which functions through the cAMP system, relaxes it. Interactions between the two second messenger systems are important in regulation of smooth muscle tone and represent an important focal point for pharmacological manipulation. Here, I have summarized the experimental evidence in support of the hypothesis that the cross talk between cAMP and the PPI cascade could constitute a biochemical correlate for this functional antagonism. Recent studies suggest that cAMP inhibition is on Ca²⁺ mobilization rather than myosin light chain phosphorylation. Thus, cAMP-elevating agents, which 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⁺ influx through the plasma membrane, and since a reduction in intracellular Ca²⁺ ([Ca²⁺]₁) is the underlying mechanism for cAMP-mediated relaxation, an important target for cAMP inhibition would be either to inhibit IP₃ production or to stimulate IP₃ inactivation. In the iris sphincter and other nonvascular smooth muscle there is reasonable experimental evidence that shows that cAMP inhibits phospholipase C activation and stimulates IP₃ 3-kinase activity, both of which can result in: (i) reduction in IP₃ concentrations and (ii) reduction in IP₃-dependent Ca²⁺ mobilization, which may lead to muscle relaxation. In addition to IP₃-induced Ca²⁺ mobilization, changes in [Ca²⁺]₁ are the result of the interplay of many processes which may also serve as potential sites for cAMP inhibition. A great deal of progress has been made on the cross talk between cAMP and the PPI signaling cascade in the past decade, and there will be more made on the regulation of the second messenger systems and their involvement in smooth muscle tone in the coming years.