The effect of epidermal growth factor on membrane potential. Rapid hyperpolarization followed by persistent fluctuations.

The effects of epidermal growth factor (EGF) on membrane potential were investigated in suspensions of the following three cell types endowed with a large complement of specific receptors: EGFR-T17 (a clone of mouse NIH-3T3 fibroblasts overexpressing EGF receptors); A431 and KB (two human carcinoma lines). In all these lines EGF induced a rapid and marked hyperpolarization constituted by an initial peak (in all three cell lines) and a subsequent sustained plateau phase, concomitant with the well-known increase of [Ca2+]i. The time course and phorbol ester inhibitability of the membrane potential effects were the same as for the [Ca2+]i response. Experiments with Na+-free and chloride-free media excluded a major role of the latter ions in the EGF-induced hyperpolarization. In contrast, experiments with high K+ media, with the monovalent cation ionophore gramicidin and with Ca2+-free media together with either a Ca2+ ionophore (ionomycin, in A431 and EGFR-T17), or an agonist (bradykinin, in A431) addressed to a receptor coupled to phosphoinositide hydrolysis, were consistent with the involvement of Ca2+-activated K+ channels. The EGF-induced hyperpolarization was completely blocked by the K+ channel blocker, quinidine, and unaffected by a variety of other drugs. Patch clamping of individual EGFR-T17 cells confirmed the initial hyperpolarization (from approximately -30 mV, the resting potential, to -60, -80 mV) was due to activation of an outward current. This initial hyperpolarization was followed by fluctuations (period approximately 1 min) persisting as long as the cells could be analyzed. Thus, the changes of membrane potential appear to be not only novel members of the group of early events triggered by EGF in target cells but also long-lasting effects of the growth factor, which continue for unexpectedly long periods of time after EGF application

Nanoparticles and potential neurotoxicity: focus on molecular mechanisms

The last decades have seen an explosive increase in the development of nanoparticles and in their use in consumer, industrial and medical applications. Their fast diffusion has also raised widespread concern about the potential toxic effects on living organisms, including humans: at the nanoscale, they can interact with subcellular components such as membranes, proteins, lipids, nucleic acids, thus inducing unpredicted functional perturbations in cells and tissues. The nervous tissue is a particular sensitive target, because its cellular components (mainly neurons and glial cells) are tightly regulated and metabolically exigent biological entities. While the literature on the potential toxicity of nanoparticles has grown in parallel with their utilization, the available data on neurotoxicity are less abundant. In particular, information on the neuronal molecular targets of nanoparticles is still largely incomplete. A better understanding of this issue is highly relevant for the rational and controlled design of nanoparticles, both for their general utilization and more specifically for their use in the promising field of nanoneuromedicine. In this review, we will discuss the available information on the mechanisms involved in the interaction between nanoobjects and cells of the nervous system, focusing on the known molecular actors, both at the plasma membrane and in intracellular compartments