Astrocyte swelling is observed in different types of brain injury including hepatic encephalopathy (HE). This study investigates the role of astrocyte swelling on Zn2+ homeostasis in hypoosmotically treated astrocytes by using the Zn2+ indicators Newport-Green, Zinquin, and RhodZin-3. Hypoosmolarity (205 mosmol/L) led to a persistent increase of the intracellular "free" Zn2+ concentration [Zn2+](i) within 15 min, which was reversible after reinstitution of normoosmolarity (305 mosmol/L). The hypoosmotic [Zn2+](i) increase was abolished in the presence of the Zn2+ chelator TPEN, the NMDA receptor antagonists MK-801 and AP5, the antioxidant epigallocatechin gallate, and the nitric oxide synthase inhibitors L-NMMA and TRIM. Hypoosmolarity triggered nuclear accumulation of the metal response element-binding transcription factor MTF-1 and the specificity protein Sp1 and expression of the mRNAs encoding metallothionein and the Sp1-regulated peripheral-type benzodiazepine receptor (PBR). These effects were abolished by the Zn2+ chelator TPEN. The data suggest that astrocyte swelling affects gene expression by modulation of [Zn2+](i). Whereas Zn2+-dependent upregulation of metallothionein may help to counteract excessive astrocyte swelling and production of reactive oxygen and nitrogen oxide species, stimulation of PBR expression may augment HE development.

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The heat shock response is a highly conserved process essential for surviving environmental stress, including extremes of temperature. To investigate whether heat shock has an impact on intracellular Zn(2+) homeostasis, cells were subjected to heat shock, and subsequently the intracellular free zinc concentration was investigated. Sublethal heat shock induced a temperature-dependent and transient intracellular Zn(2+) release that was repeatable after 24 h. The free zinc was localized in round-shaped nuclear bodies identified as nucleoli. Metallothionein, the main cellular zinc storing protein, was found to be not functionally essential for this heat-shock-induced effect. No significant oxidative stress within the cells was detected after heat shock. Cold shock and subsequent rewarming did not result in disturbed intracellular zinc homeostasis. These results show that heat shock and cold shock differ with respect to intracellular Zn(2+) release. A role for zinc as signaling ion during fever is conceivable.