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In addition to xenobiotics and several other endogenous metabolites, multidrug-resistance proteins (MRPs) extrude the second-messenger cAMP from various cells. Pharmacological and/or genetic inactivation of MRPs has been shown to augment intracellular cAMP signaling, an effect assumed to be a direct consequence of the blockade of cAMP extrusion. Here we provide evidence that the augmented intracellular cAMP levels are not due exclusively to the prevention of cAMP efflux because MRP inactivation is also associated with reduced cAMP degradation by phosphodiesterases (PDEs). Several prototypical MRP inhibitors block PDE activity at concentrations widely used to inhibit MRPs. Their dose-dependent effects in several paradigms of cAMP signaling are more consistent with their potency in inhibiting PDEs than MRPs. Moreover, genetic manipulation of MRP expression results in concomitant changes in PDE activity and protein levels, thus affecting cAMP degradation in parallel with cAMP efflux. These findings suggest that the effects of MRP inactivation on intracellular cAMP levels reported previously may be due in part to reduced degradation by PDEs and identify MRP-dependent transport mechanisms as novel regulators of cellular PDE expression levels. Mathematical simulations of cAMP signaling predict that selective ablation of MRP-dependent cAMP efflux per se does not affect bulk cytosolic cAMP levels, but may control cAMP levels in restricted submembrane compartments that are defined by small volume, high MRP activity, limited PDE activity, and limited exchange of cAMP with the bulk-cytosolic cAMP pool. Whether this regulation occurs in cells remains to be confirmed experimentally under conditions that do not affect PDE activity.

Inactivation of Multidrug Resistance Proteins Disrupts Both Cellular Extrusion and Intracellular Degradation of cAMP