Na⁺/Ca²⁺exchanger 3 (NCX3), one of the three isoforms of the NCX family, is highly expressed in the brain and is involved in the maintenance of intracellular Na⁺and Ca²⁺homeostasis. Interestingly, whereas the function of NCX3 under physiological conditions has been determined, its role under anoxia is still unknown. To assess NCX3 role in cerebral ischemia, we exposed ncx3−/− mice to transient middle cerebral artery occlusion followed by reperfusion. In addition, to evaluate the effect of ncx3 ablation on neuronal survival, organotypic hippocampal cultures and primary cortical neurons from ncx3−/− mice were subjected to oxygen glucose deprivation (OGD) plus reoxygenation. Here we report that ncx3 gene suppression leads to a worsening of brain damage after focal ischemia and to a massive neuronal death in all the hippocampal fields of organotypic cultures as well as in cortical neurons from ncx3−/− mice exposed to OGD plus reoxygenation. In addition, in ncx3−/− cortical neurons exposed to hypoxia, NCX currents, recorded in the reverse mode of operation, were significantly lower than those detected in ncx3+/+. From these results, NCX3 protein emerges as a new molecular target that may have a potential therapeutic value in modulating cerebral ischemia.

Increasing evidence suggests that a continuous release of histamine from mast cells occurs in the airways of asthmatic patients and that histamine may modulate functions of other inflammatory cells such as macrophages. In the present study histamine (10⁻⁹–10⁻⁶ M) increased in a concentration-dependent fashion the basal release of β-glucuronidase (EC₅₀ = 8.2 ± 3.5 × 10⁻⁹ M) and IL-6 (EC₅₀ = 9.3 ± 2.9 × 10⁻⁸ M) from human lung macrophages. Enhancement of β-glucuronidase release induced by histamine was evident after 30 min and peaked at 90 min, whereas that of IL-6 required 2–6 h of incubation. These effects were reproduced by the H₁ agonist (6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptane carboxamide but not by the H₂ agonist dimaprit. Furthermore, histamine induced a concentration-dependent increase of intracellular Ca²⁺ concentrations ([Ca²⁺]_i) that followed three types of response, one characterized by a rapid increase, a second in which [Ca²⁺]_i displays a slow but progressive increase, and a third characterized by an oscillatory pattern. Histamine-induced β-glucuronidase and IL-6 release and [Ca²⁺]_i elevation were inhibited by the selective H₁ antagonist fexofenadine (10⁻⁷–10⁻⁴ M), but not by the H₂ antagonist ranitidine. Inhibition of histamine-induced β-glucuronidase and IL-6 release by fexofenadine was concentration dependent and displayed the characteristics of a competitive antagonism (K_d = 89 nM). These data demonstrate that histamine induces exocytosis and IL-6 production from human macrophages by activating H₁ receptor and by increasing [Ca²⁺]_i and they suggest that histamine may play a relevant role in the long-term sustainment of allergic inflammation in the airways.

Changes in intracellular [Ca²⁺]_i levels have been shown to influence developmental processes that accompany the transition of human oligodendrocyte precursor cells (OPCs) into mature myelinating oligodendrocytes and are required for the initiation of the myelination and re-myelination processes. In the present study, we explored whether calcium signals mediated by the selective sodium calcium exchanger (NCX) family members NCX1, NCX2, and NCX3, play a role in oligodendrocyte maturation. Functional studies, as well as mRNA and protein expression analyses, revealed that NCX1 and NCX3, but not NCX2, were divergently modulated during OPC differentiation into oligodendrocyte phenotype. In fact, whereas NCX1 was downregulated, NCX3 was strongly upregulated during oligodendrocyte development. The importance of calcium signaling mediated by NCX3 during oligodendrocyte maturation was supported by several findings. Indeed, whereas knocking down the NCX3 isoform in OPCs prevented the upregulation of the myelin protein markers 2′,3′-cyclic nucleotide-3′-phosphodiesterase (CNPase) and myelin basic protein (MBP), its overexpression induced an upregulation of CNPase and MBP. Furthermore, NCX3-knockout mice showed not only a reduced size of spinal cord but also marked hypo-myelination, as revealed by decrease in MBP expression and by an accompanying increase in OPC number. Collectively, our findings indicate that calcium signaling mediated by NCX3 has a crucial role in oligodendrocyte maturation and myelin formation.