Control of Ca2+ and metabolic homeostasis by the Na+/Ca2+ exchangers (NCXs) in health and disease.

Spatial and temporal control of calcium (Ca2+) levels is essential for the background rhythms and responses of living cells to environmental stimuli. Whatever other regulators a given cellular activity may have, localized and wider scale Ca2+ events (sparks, transients, and waves) are hierarchical determinants of fundamental processes such as cell contraction, excitability, growth, metabolism and survival. Different cell types express specific channels, pumps and exchangers to efficiently generate and adapt Ca2+ patterns to cell requirements. The Na+/Ca2+ exchangers (NCXs) in particular contribute to Ca2+ homeostasis by buffering intracellular Ca2+ loads according to the electrochemical gradients of substrate ions - i.e., Ca2+ and sodium (Na+) - and under a dynamic control of redundant regulatory processes. An interesting feature of NCX emerges from the strict relationship that connects transporter activity with cell metabolism: on the one hand NCX operates under constant control of ATP-dependent regulatory processes, on the other hand the ion fluxes generated through NCX provide mechanistic support for the Na+-driven uptake of glutamate and Ca2+ influx to fuel mitochondrial respiration. Proof of concept evidence highlights therapeutic potential of preserving a timed and balanced NCX activity in a growing rate of diseases (including excitability, neurodegenerative, and proliferative disorders) because of an improved ability of stressed cells to safely maintain ion gradients and mitochondrial bioenergetics. Here, we will summarize and review recent works that have focused on the pathophysiological roles of NCXs in balancing the two-way relationship between Ca2+ signals and metabolism.

Endocytosis and the Participation of Glycosaminoglycans Are Important to the Mechanism of Cell Death Induced by ß-Hairpin Antimicrobial Peptides.

The cytotoxic mode of action of four antimicrobial peptides (AMPs) (gomesin, tachyplesin, protegrin, and polyphemusin) against a HeLa cell tumor model is discussed. A study of cell death by AMP stimulation revealed some similarities, including annexin-V externalization, reduction of mitochondrial potential, insensitivity against inhibitors of cell death, and membrane permeabilization. Evaluation of signaling proteins and gene expression that control cell death revealed wide variation in the responses to AMPs. However, the ability to cross cell membranes emerged as an important characteristic of AMP-dependent cell death, where endocytosis mediated by dynamin is a common mechanism. Furthermore, the affinity between AMPs and glycosaminoglycans (GAGs) and GAG participation in the cytotoxicity of AMPs were verified. The results show that, despite their primary and secondary structure homology, these peptides present different modes of action, but endocytosis and GAG participation are an important and common mechanism of cytotoxicity for ß-hairpin peptides.