Inactivation of multidrug resistance proteins disrupts both cellular extrusion and intracellular degradation of cAMP.

ABSTRACT: 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 inhibitin

SUBMITTER: Xie M 

PROVIDER: S-EPMC3141887 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature