TY - JOUR T1 - Dependence of multidrug resistance protein-mediated cyclic nucleotide efflux on the background sodium conductance JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/mol.109.059386 SP - mol.109.059386 AU - Marek Kucka AU - Karla Kretschmannova AU - Takayo Murano AU - Chung-Pu Wu AU - Hana Zemkova AU - Suresh V Ambudkar AU - Stanko S Stojilkovic Y1 - 2009/01/01 UR - http://molpharm.aspetjournals.org/content/early/2009/11/10/mol.109.059386.abstract N2 - Anterior pituitary cells fire action potentials and release cyclic nucleotides both spontaneously and in response to agonist stimulation, but the relationship between electrical activity and cyclic nucleotide efflux has not been studied. In these cells, a tetrodotoxin-resistant background Na+ conductance is critical for firing of action potentials and multidrug resistance proteins MRP4 and MRP5 contribute to cyclic nucleotide efflux. Here, we show that abolition of the background Na+ conductance in rat pituitary cells by complete or partial replacement of extracellular Na+ with organic cations or sucrose induced a rapid and reversible hyperpolarization of cell membranes and inhibition of action potential firing, accompanied by a rapid inhibition of cyclic nucleotide efflux. Valinomycin-induced hyperpolarization of plasma membranes also inhibited cyclic nucleotide efflux, whereas depolarization of cell membranes induced by inhibition of Ca2+ influx or stimulation of Na+ influx by gramicidin was accompanied by a facilitation of cyclic nucleotide efflux. In contrast, inhibition of cyclic nucleotide efflux by probenecid did not affect the background Na+ conductance. In HEK293 cells stably transfected with human MRP4 or MRP5, replacement of bath Na+ with organic cations also hyperpolarized the cell membranes and inhibited cyclic nucleotide efflux. In these cells, the Na+/H+ antiporter monensin did not affect the membrane potential and was practically ineffective in altering cyclic nucleotide efflux. In both pituitary and MRP4 and MRP5 expressing cells, MK571 inhibited cyclic nucleotide efflux. These results indicate that the MRP4/5-mediated cyclic nucleotide efflux can be rapidly modulated by membrane potential determined by the background Na+ conductance.The American Society for Pharmacology and Experimental Therapeutics ER -