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¹ European Neuroscience Institute-Göttingen, Waldweg 33, 37073 Göttingen, Germany

Cl^– ions are known regulators of Ca²⁺-dependent secretory activity in many endocrine cells. The suggested mechanisms of Cl^– action involve the modulation of GTP-binding proteins, voltage-activated calcium channels or maturation of secretory vesicles. We examined the role of cytosolic Cl^– ([Cl^–]_i) and Cl^– currents in the regulation of secretory activity in mouse melanotrophs from fresh pituitary tissue slices by using the whole-cell patch-clamp. We confirmed that elevated [Cl^–]_i augments Ca^2–-dependent exocytosis and showed that Cl^– acts on secretory vesicle maturation. The latter process was abolished by a V-type H^–-ATPase blocker (bafilomycin), intracellular 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a Cl^– channel blocker, and tolbutamide, a sulphonylurea implicated in secretory vesicle maturation. In a small subset of cells, block of plasmalemmal Cl^– current by DIDS reversibly enhanced endocytosis. The direct activation of G-proteins by GTP--S, a non-hydrolysable GTP analogue, did not restore the impaired secretion observed in low [Cl^–]_i conditions. The amplitude of voltage-activated calcium currents was unaffected by the [Cl^–]_i. Furthermore, two Cl^–-permeable channels, calcium-activated Cl^– channels and GABA_A receptors, appeared as major regulators of intracellular Cl^– homeostasis. In conclusion, the predominant underlying mechanism of Cl^– action is mediated by intracellular Cl^– fluxes during vesicle maturation, rather than activation of G-proteins or modulation of voltage-activated Ca²⁺ channels.

(Received 20 April 2005; accepted after revision 9 May 2005; first published online 12 May 2005)
Corresponding author M. Rupnik: European Neuroscience Institute-Göttingen, Waldweg 33, 37073 Göttingen, Germany. Email: mrupnik{at}gwdg.de

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