The basal (swelling-induced) and receptor-stimulated effluxes of 125 I Ϫ and taurine have been monitored to determine whether these two osmolytes are released from human SH-SY5Y cells under hypotonic conditions via common or distinct mechanisms. Under basal conditions, both 125 I Ϫ (used as a tracer for Cl Ϫ ) and taurine were released from the cells in a volumedependent manner. The addition of thrombin, mediated via the proteinase-activated receptor-1 (PAR-1) subtype, significantly enhanced the release of both 125 I Ϫ and taurine (3-6-fold) and also increased the threshold osmolarity for efflux of these osmolytes ("set-point") from 200 to 290 mOsM. Inclusion of a variety of broad-spectrum anion channel blockers and of 4-[(2-butyl-6,7-dichloro-2-cyclopentyl-2,3-dihydro-1-oxo-1H-inden-5-yl)oxy]butanoic acid attenuated the release of both 125 I Ϫ and taurine under basal and receptor-stimulated conditions. Basal release of 125 I Ϫ and taurine was independent of Ca 2ϩ or the activity of protein kinase C (PKC). However, although PAR-1-stimulated taurine efflux was attenuated by either a depletion of intracellular Ca 2ϩ or inhibition of PKC by chelerythrine, the enhanced release of 125 I Ϫ was independent of both parameters. Stimulated efflux of 125 I Ϫ after activation of muscarinic cholinergic receptors was also markedly less dependent on Ca 2ϩ availability and PKC activity than that observed for taurine release. These results indicate that, although the osmosensitive release of these two osmolytes from SH-SY5Y cells may occur via pharmacologically similar membrane channels, the receptor-mediated release of 125 I Ϫ and taurine is differentially regulated by PKC activity and Ca 2ϩ availability.Cell volume is constantly subject to change as a consequence of solute accumulation, oxidative metabolism, or fluctuations in the osmolarity of the extracellular fluid. To survive, cells need to regulate their volume within relatively narrow limits, and this homeostatic mechanism is of particular importance to the brain because of the restrictions of the skull. A common cause of brain swelling is hyponatremia, a condition that disproportionately affects the elderly, infants, marathon runners, and military personnel (Upadhyay et al., 2006). Hyponatremia is associated with a variety of neurological symptoms, such as disorientation, mental confusion, and seizures (Kimelberg, 2000;Pasantes-Morales et al., 2000.In response to hypotonic stress, cells swell with a magnitude proportional to the reduction in osmolarity. This is followed by a homeostatic mechanism termed regulatory volume decrease (RVD) that involves the extrusion of intracellular ions such as K ϩ , Cl Ϫ , and a number of organic osmolytes, which together facilitate the loss of water to normalize cell volume (Pasantes-Morales et al., 2000). Inorganic ions constitute two-thirds of the osmolytes released during RVD, and the remainder are accounted for by "compatible" organic osmolytes such as polyols, methylamines, and amino acids. Of these, taurine, an amino acid...

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