Zinc is concentrated in certain CNS excitatory tracts, especially in hippocampal mossy fibres where it has been suggested to modulate synaptic transmission and plasticity. Using rat mossy fibre synaptosomes depolarized by 4-aminopyridine, we show here that low zinc concentrations restore the membrane potential and reduce glutamate release. Both effects arose from activation of ATP-sensitive potassium channels (K ATP ), since they were mimicked by the K ATP opener diazoxide and antagonized by the K ATP blocker tolbutamide. Using recombinant channels expressed in COS-7 cells, we confirmed that micromolar zinc did activate K ATP of the type found in hippocampus. We tested the hypothesis that this action of zinc could be beneficial during an ischaemic challenge by using organotypic hippocampal slice cultures. When zinc was applied at micromolar concentrations during a brief anoxichypoglycaemic episode, it significantly attenuated the ensuing neuronal death, whereas chelation of endogenous zinc markedly aggravated cell damage. Protective effect of zinc was mediated through K ATP , as was shown by using the opener diazoxide and the blocker tolbutamide. Thus, by activating pre-synaptic K ATP channels, zinc protects neurones from hyper-excitation, excessive transmitter release and exitotoxicity, and may thus act as an endogenous neuroprotector in conditions such as epilepsy or stroke.

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Herein, we show that TNF exerts a pH‐dependent increase in membrane conductance in primary lung microvascular endothelial cells and peritoneal macrophages. This effect was TNF receptor‐independent, since it also occurred in cells isolated from mice deficient in both types of TNF receptors. A TNF mutant in which the three amino acids critical for the lectin‐like activity were replaced by an alanine did not show any significant effect on membrane conductance. Moreover, a synthetic 17‐amino acid peptide of TNF, which was previously shown to exert lectin‐like activity, also increased the ion permeability in these cells. The amiloride sensitivity of the observed activity suggests a binding of TNF to an endogenousion channel rather than channel formation by TNF itself. This may have important implications in mechanisms of TNF‐mediated vascular pathology.

The effects of zinc (Zn2+) on excitability and ionic conductances were analysed on RINm5F insulinoma cells under whole‐cell and outside‐out patch‐clamp recording conditions. We found that extracellular application of 10‐20 μM Zn2+ induced a reversible abolition of Ca2+ action potential firing, which was accompanied by an hyperpolarisation of the resting membrane potential. Higher concentrations of Zn2+, in the tens to hundreds micromolar range, induced a reversible reduction of voltage‐gated Ca2+ and, to a lesser extent, K+ currents. Low‐voltage‐activated Ca2+ currents were more sensitive to Zn2+ block than high voltage‐activated Ca2+ currents. The Zn2+‐induced hyperpolarisation arose from a dose‐dependent increase in a voltage‐independent K+ conductance that was pharmacologically identified as an ATP‐sensitive K+ (KATP) conductance. The effect was rapid in onset, readily reversible, voltage independent, and related to intracellular ATP concentration. In the presence of 1 mM intracellular ATP, half‐maximal activation of KATP channels was obtained with extracellular application of 1.7 μM Zn2+. Single channel analysis revealed that extracellular Zn2+ increased the KATP channel open‐state probability with no change in the single channel conductance. Our data support the hypothesis that Zn2+ binding to KATP protein subunits results in an activation of the channels, therefore regulating the resting membrane potential and decreasing the excitability of RINm5F cells. Taken together, our results suggest that Zn2+ can influence insulin secretion in pancreatic β‐cells through a negative feedback loop, involving both KATP and voltage‐gated conductances.