Voltage-dependent anion channels (VDAC) in the plasma membrane play a critical role in apoptosis in differentiated hippocampal neurons but not in neural stem cells

Abstract

One of the earliest morphological changes occurring in apoptosis is cell shrinkage associated with an increased efflux of K(+) and Cl(-) ions. Block of K(+) or Cl(-) channels prevents cell shrinkage and death. Recently, we found evidences for the activation of a voltage-dependent anion channel in the plasma membrane (pl-VDAC) of a hippocampal cell line undergoing apoptosis. Nothing is known on pl-VDAC in apoptotic cell death of neural cells at different stages of differentiation. We have addressed this issue in primary cultures of differentiated hippocampal neurons and embryonic neural stem cells (NSCs). In control hippocampal neurons, pl-VDAC is closed but acts as an NADH-ferricyanide reductase, while in apoptotic neurons, pl-VDAC is opened and the enzymatic activity is increased. Anti-VDAC antibodies block pl-VDAC and prevent apoptosis, as well as the increase in enzymatic activity. Conversely, in NSCs, pl-VDAC is scarcely seen and there is no NADH-ferricyanide reductase activity. In agreement, anti-VDAC antibodies do not affect the apoptotic process. Instead, we find activation of a Na(+) channel that has low voltage dependency, a conductance of 26 pS, and is blocked by amiloride, which also prevents apoptosis. Thus, it appears that activation of pl-VDAC during apoptosis is a critical event in differentiated neurons, but not in NSCs.

The Voltage-dependent Anion Channel 1 Mediates Amyloid β Toxicity and Represents a Potential Target for Alzheimer Disease Therapy

“…Indeed, plasma membrane-bound VDAC1 was found in various cells, including the post-synaptic membrane fraction from brain (25), and in caveolae and caveolae-like domains (26). Still, this form of the protein remains a matter of dispute (36). The involvement of plVDAC1 in AD was proposed based on VDAC1 being abundant in caveolae and prominent in the dystrophic neurites of senile plaques (26) as well as because of the inhibition of A␤-induced apoptosis by anti-VDAC antibodies (37).…”

Fluorescent dyes as a reliable tool in P2X7 receptor-associated pore studies

“…In this context, Thompson recorded pannexin-1 hemichannel activity and observed at least two distinct conductance levels (Thompson et al 2006). Similarly, high subconductance stages have been observed in connexin 43 hemichannel (Contreras et al 2003;Carnarius et al 2012) and maxi anion (Schwarze and Kolb 1984;Olesen and Bundgaard 1992;Dutta et al 2004;Akanda et al 2008) opening. Additionally, a few number of papers studied the electrophysiological properties in these pore-forming proteins and used fluorescent dyes in these studies.…”

Membrane lipid rafts and estrogenic signalling: a functional role in the modulation of cell homeostasis

“…VDAC has been shown to play a critical role in the modulation of Abinduced toxicity and in the extrinsic apoptosis pathway in differentiated hippocampal neurons [62]. In fact, Ab peptide interaction with specific sites of the plasma membrane such as lipid rafts may contribute to VDAC opening and activation, provoking intracellular increase of Ca 2 levels ultimately leading to extrinsic apoptosis [62]. E2 can contribute to neuroprotection by VDAC phosphorylation, in order to maintain the channel in an unactivated (closing) state.…”

“…ERa in these microdomains participates in the modulation of amyloid-beta (Ab) induced injury in a multicomplex with other molecules, such as a voltage-dependent anion channel (VDAC), as a part of a 'signalosome' that may activate some intracellular signal transduction. VDAC has been shown to play a critical role in the modulation of Abinduced toxicity and in the extrinsic apoptosis pathway in differentiated hippocampal neurons [62]. In fact, Ab peptide interaction with specific sites of the plasma membrane such as lipid rafts may contribute to VDAC opening and activation, provoking intracellular increase of Ca 2 levels ultimately leading to extrinsic apoptosis [62].…”