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CELLULAR AND MOLECULAR

Prostanoid Receptors Regulate the Volume-Sensitive Efflux of Osmolytes from Murine Fibroblasts via a Cyclic AMP-Dependent Mechanism

Molecular and Behavioral Neuroscience Institute (A.M.H., S.K.F.) and Department of Pharmacology (D.J.F., S.K.F.), University of Michigan, Ann Arbor, Michigan

The ability of prostanoid receptors to regulate the volume-dependent efflux of the organic osmolyte taurine from murine fibroblasts (L cells) via a cAMP-dependent mechanism has been examined. Incubation of L cells under hypoosmotic conditions resulted in a time-dependent efflux of taurine, the threshold of release occurring at 250 mOsM. Addition of prostaglandin E₁ (PGE₁) potently (EC₅₀ = 2.5 nM) enhanced the volume-dependent efflux of taurine at all time points examined and increased the threshold for osmolyte release to 290 mOsM. Maximal PGE₁ stimulation (250–300% of basal) of taurine release was observed at 250 mOsM. Of the PGE analogs tested, only the EP₂-selective agonist butaprost (9-oxo-11,16S-dihydroxy-17-cyclobutyl-prost-13E-en-1-oic acid) was able to enhance taurine efflux. Inclusion of 1,9-dideoxyfoskolin, 5-nitro-2-(3-phenylpropylamino) benzoic acid, or 4-[(2-butyl-6,7-dicloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]-butanoic acid blocked the ability of PGE₁ to enhance taurine release, indicating the mediation of a volume-sensitive organic osmolyte and anion channel. The ability of PGE₁ to increase osmolyte release from L cells was mimicked by the addition of agents that inhibit cAMP breakdown, directly activate adenylyl cyclase, or are cell-permeant analogs of cAMP. Taurine release elicited by either PGE₁ or 8-(4-chlorophenylthio)-cAMP was attenuated by >70% in L cells that had been stably transfected with a mutant regulatory subunit of cAMP-dependent protein kinase (PKA). PGE₁ stimulation of taurine efflux was not attenuated by either depletion of intracellular calcium or inhibition of protein kinase C. The results indicate that activation of prostanoid receptors on murine fibroblasts enhances osmolyte release via a cAMP and PKA-dependent mechanism.

Address correspondence to: Dr. Stephen K. Fisher, Molecular and Behavioral Neuroscience Institute, University of Michigan, 5039 Biomedical Science Research Bldg., Ann Arbor, MI 48109-2200. E-mail: skfisher{at}umich.edu

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				T. A. Cheema and S. K. Fisher Cholesterol Regulates Volume-Sensitive Osmolyte Efflux from Human SH-SY5Y Neuroblastoma Cells following Receptor Activation J. Pharmacol. Exp. Ther., February 1, 2008; 324(2): 648 - 657. [Abstract] [Full Text] [PDF]