G-Protein-Coupled Inwardly Rectifying Potassium (GIRK) Channel Activation by the p75 Neurotrophin Receptor Is Required for Amyloid β Toxicity

Abstract

Alzheimer's disease is characterized by cognitive decline, neuronal degeneration, and the accumulation of amyloid-beta (Aβ). Although, the neurotoxic Aβ peptide is widely believed to trigger neuronal dysfunction and degeneration in Alzheimer's disease, the mechanism by which this occurs is poorly defined. Here we describe a novel, Aβ-triggered apoptotic pathway in which Aβ treatment leads to the upregulation of G-protein activated inwardly rectifying potassium (GIRK/Kir3) channels, causing potassium efflux from neurons and Aβ-mediated apoptosis. Although, GIRK channel activity is required for Aβ-induced neuronal degeneration, we show that it is not sufficient, with coincident signaling by the p75 neurotrophin receptor (p75NTR) also required for potassium efflux and cell death. Our results identify a novel role for GIRK channels in mediating apoptosis, and provide a previously missing mechanistic link between the excitotoxicity of Aβ and its ability to trigger cell death pathways, such as that mediated by p75NTR. We propose that this death-signaling pathway contributes to the dysfunction of neurons in Alzheimer's disease and is responsible for their eventual degeneration.

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

“…Then, Aβ 1–42 modulation of GirK channel might be found analyzing specific regions of the hippocampus (immunohistochemical approach), but it could not be observed in the hippocampus as a whole (western blot analysis). Nevertheless, present data suggest that GirK channels can be taken into account to explain some of the effects of Aβ 1–42 (May et al, ; Nava‐Mesa et al, ; Sanchez‐Rodriguez et al, , ).…”

“…However, in this study, we found that in hippocampal slices incubated with Aβ 1–42 , protein expression pattern for GIRK1 and 2 subunits did not change. It has been reported that excitotoxic oligomeric Aβ 1–42 may cause a rapid redistribution of existing GirK subunits to the membrane surface (May et al, ), which could explain that protein expression did not seem to change. On the other hand, the immunohistochemical analysis of GIRK1 subunit in the dorsal hippocampus of our different experimental groups showed a significant modulation of GIRK1 protein expression levels, increasing when channel is blocked by TQ, whereas decreasing when opened by ML297, as expected for neuronal drug sensitization and desensitization processes, respectively (Golan, Armstrong, & A.W., A., ).…”

“…Given that Aβ has been shown to alter GirK channels at the molecular (May et al, ; Mayordomo‐Cava et al, ) and synaptic (Nava‐Mesa et al, ) levels, we asked whether blocking of GirK‐dependent signaling with TQ would interfere with synaptic plasticity depression induced by Aβ 1–42 . As lack of GirK channels has been shown to be deleterious for cognition (Slesinger et al, ) we first evaluated the effect of TQ (0.5 μM) on LTP induction.…”

“…Aβ 25–35 , the active fragment of Aβ peptide, and Aβ 1–42 , a more relevant specie in AD patients, seem to share neurophysiopathological mechanisms as both induce an imbalance in the excitatory/inhibitory neurotransmission in the hippocampus that causes aberrant activity (Gutierrez‐Lerma, Ordaz, & Pena‐Ortega, ). In addition, pathological GirK channel activity induced by Aβ 1–42 has been related to neuronal degeneration and apoptosis mechanisms (May et al, ). These data suggest GirK as one of the putative targets on which Aβ could be acting on.…”

Unraveling the Role of Inwardly Rectifying Potassium Channels in the Hippocampus of an Aβ(1–42)-Infused Rat Model of Alzheimer’s Disease

“…We can speculate that this evidence may be due to two contrasting effects of Aβ on these channels in a more complex neuronal network. Indeed, it has been reported that this peptide led to a GIRK3 channel upregulation, which resulted in K + efflux from neurons triggering, thus, the Aβ-mediated apoptotic pathway [26]. On the contrary, other authors reported an opposite effect of Aβ in which it modulated GIRK3 expression by downregulating these channels [14].…”