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The last decade has seen the rapid development of research investigating the molecular mechanisms whereby hormones, peptide growth factors and cytokines regulate cell metabolism, differentiation and proliferation. One general signalling mechanism used to transfer the information delivered by agonists into appropriate intracellular compartments involves the rapid Ca2+ redistribution throughout the cell, which results in transient elevations of the cytosolic free Ca2+ concentration. Ca2+ signals are required for a number of cellular processes including the activation of nuclear processes such as gene transcription and cell cycle events. The latter require that appropriate Ca2+ signals elicited in response to agonists be transduced across the nuclear envelope. It has generally been assumed that small molecules, metabolites and ions could freely diffuse across the nuclear envelope. Nevertheless several findings during the past few years have suggested that nuclear pore permeability can be regulated and that ion transport systems and ion-selective channels may exist on the nuclear membranes and regulate intranuclear processes.

The effects of different levels of inorganic mercury (Hg2+) on depolarization‐ or agonist‐stimulated Ca2+signals were studied in PC12 cells. Exposure to 50–300 nM Hg2+did not alter the resting cytosolic free Ca2+concentration ([Ca2+]i), but enhanced the Ca2+response to KCl‐induced depolarization. Patch‐clamp experiments revealed that these Hg2+concentrations increased the voltage‐dependent Ca2+current through L‐type channels. Also, Hg2+treatment amplified the intracellular [Ca2+]i transients elicited by extracellular ATP. In contrast, the Ca2+increase stimulated by bradykinin was unaffected. At slightly higher concentrations (1 to 2 μM), Hg2+caused a sustained rise of the resting [Ca2+]i. This increase did not occur in Ca2+‐free medium and was prevented by pretreatment with NiCl2or with the L‐type Ca2+channel blockers, verapamil and nifedipine. Hg2+did not mobilize Ca2+from intracellular stores sensitive to thapsigargin, 2,5‐di‐(tert‐butyl)‐benzohydroquinone, or caffeine. At 2 μM, Hg2+inhibited the [Ca2+]itransients elicited by bradykinin, ATP, or KCl‐induced depolarization. The loss of the intracellular Ca2+response to bradykinin was independent from the Ca2+overload elicited by Hg2+; instead, it was associated with inhibition of polyphosphoinositide generation. Exposure to the lower Hg2+concentrations (0.3–0.5 μM) greatly potentiated NGF‐induced PC12 cell differentiation. Conversely, treatment with 2 μM Hg2+caused cell death. Our results show that inorganic mercury has selective and different effects on Ca2+signaling in PC12 cells depending on the concentration, within a narrow range.— Rossi, A. D., Larsson, O., Manzo, L., Orrenius, S., Vahter, M., Berggren, P‐O., Nicotera, P. Modifications of Ca2+signaling by inorganic mercury in PC12 cells. FASEB J.7: 1507‐1514; 1993.

BCL-2 is a negative regulator of cell death in several systems. Here we report that bcl-2expression protects against apoptosis induced by nitric oxide (NO) donors in GT1-7 hypothalamic cells. BCL-2 significantly inhibited neuronal death caused by 200 mM S-nitrosocysteine (SNOC), 200 mM S-nitroso-N-acetyl-penicillamine (SNAP), or 1 mM 3-morpholinosydnonimine (SIN-1). To explore further the protective mechanism(s) elicited by bcl-2expression, we investigated whether BCL-2 could prevent NO-induced cleavage of poly- ADP-ribose-polymerase (PARP), which is a substrate for interleukin-1b converting enzyme (ICE)-like proteases in apoptosis. Formation of 85 and 25 kDa PARP fragments elicited by NO donors was inhibited in cells over-expressing bcl-2.