Abstract
Intracellular calcium concentration ([Ca2+]i) transients in astrocytes represent a highly plastic signaling pathway underlying the communication between neurons and glial cells. However, how this important phenomenon may be compromised in Alzheimer’s disease (AD) remains unexplored. Moreover, the involvement of several K+ channels, including KV3.4 underlying the fast-inactivating currents, has been demonstrated in several AD models. Here, the effect of KV3.4 modulation by the marine toxin blood depressing substance-I (BDS-I) extracted from Anemonia sulcata has been studied on [Ca2+]i transients in rat primary cortical astrocytes exposed to Aβ1–42 oligomers. We showed that: (1) primary cortical astrocytes expressing KV3.4 channels displayed [Ca2+]i transients depending on the occurrence of membrane potential spikes, (2) BDS-I restored, in a dose-dependent way, [Ca2+]i transients in astrocytes exposed to Aβ1–42 oligomers (5 µM/48 h) by inhibiting hyperfunctional KV3.4 channels, (3) BDS-I counteracted Ca2+ overload into the endoplasmic reticulum (ER) induced by Aβ1–42 oligomers, (4) BDS-I prevented the expression of the ER stress markers including active caspase 12 and GRP78/BiP in astrocytes treated with Aβ1–42 oligomers, and (5) BDS-I prevented Aβ1–42-induced reactive oxygen species (ROS) production and cell suffering measured as mitochondrial activity and lactate dehydrogenase (LDH) release. Collectively, we proposed that the marine toxin BDS-I, by inhibiting the hyperfunctional KV3.4 channels and restoring [Ca2+]i oscillation frequency, prevented Aβ1–42-induced ER stress and cell suffering in astrocytes.
Highlights
In the present study, we have investigated the effect of the Anemonia sulcata toxin blood depressing substance-I (BDS-I) blocking KV 3.4 channel subunits on [Ca2+ ]i transients, endoplasmic reticulum (ER) Ca2+ signaling, reactive oxygen species (ROS) production, and cell survival in cortical astrocytes exposed to Aβ1–42 oligomers
To examine cytoskeleton rearrangement after exposure to Aβ1–42 oligomers, F-actin cytoskeleton was stained in primary cortical astrocytes with the actin-binding dye phalloidin
The present study shows that the Anemonia sulcata toxin BDS-I restored spontaneous present in study shows that the Anemonia sulcata
Summary
Astrocytes continuously handle gliotransmitters like purines, D-serine, and glutamate, whose uptake and release are regulated by the frequency of their intracellular calcium concentration ([Ca2+ ]i ) transients, a complex ionic phenomenon involving both extracellular and intracellular compartments including the endoplasmic reticulum (ER). The extent of this electric phenomenon is driven by several molecular mechanisms residing in astrocytes [11,12,13]. [Ca2+ ]i transients may be generated by the release of Ca2+ from ER [14] or by an influx from the extracellular space through ionotropic receptors or plasma membrane channels [12]. While the origin of ERmediated Ca2+ transients seems to be predominant in the soma, the plasmalemmal-located entry mechanisms are involved at the level of astrocyte processes [13,15,16,17,18]
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