title: Dependence of multidrug resistance protein-mediated cyclic nucleotide efflux on the background sodium conductance.
abstract: 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 N(+) conductance is critical for firing of action potentials, and multidrug resistance proteins (MRPs) 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 the inhibition of Ca(2+) 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 human embryonic kidney 293 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, 3-[[3-[2-(7-chloroquinolin-2-yl)vinyl]phenyl]-(2-dimethylcarbamoylethylsulfanyl)methylsulfanyl] propionic acid (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.
authors.affiliation: National Institute of Child Health and Human Development, Bethesda, MD 20892-4510, USA.
authors.forename: Marek
authors.initials: M
authors.lastname: Kucka
authors.forename: Karla
authors.initials: K
authors.lastname: Kretschmannova
authors.forename: Takayo
authors.initials: T
authors.lastname: Murano
authors.forename: Chung-Pu
authors.initials: CP
authors.lastname: Wu
authors.forename: Hana
authors.initials: H
authors.lastname: Zemkova
authors.forename: Suresh V
authors.initials: SV
authors.lastname: Ambudkar
authors.forename: Stanko S
authors.initials: SS
authors.lastname: Stojilkovic
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000502:physiology; D000818:Animals; D002460:Cell Line; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D008564:Membrane Potentials / Q000502:physiology*; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000502:physiology*; D009712:Nucleotides, Cyclic / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010902:Pituitary Gland / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012964:Sodium / Q000737:chemistry / Q000502:physiology*
chemical_list: D018528:ATP-Binding Cassette Transporters; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009712:Nucleotides, Cyclic; D012964:Sodium; C435500:ABCC11 protein, human; C073492:ABCC4 protein, human; C120809:ABCC5 protein, human