In Alzheimer's disease, accumulation of soluble oligomers of β-amyloid peptide is known to be highly toxic, causing disturbances in synaptic activity and neuronal death. Multiple studies relate these effects to increased oxidative stress and aberrant activity of calcium-permeable cation channels leading to calcium imbalance. The transient receptor potential melastatin 2 (TRPM2) channel, a Ca²⁺-permeable nonselective cation channel activated by oxidative stress, has been implicated in neurodegenerative diseases, and more recently in amyloid-induced toxicity. Here we show that the function of TRPM2 is augmented by treatment of cultured neurons with β-amyloid oligomers. Aged APP/PS1 Alzheimer's mouse model showed increased levels of endoplasmic reticulum stress markers, protein disulfide isomerase and phosphorylated eukaryotic initiation factor 2α, as well as decreased levels of the presynaptic marker synaptophysin. Elimination of TRPM2 in APP/PS1 mice corrected these abnormal responses without affecting plaque burden. These effects of TRPM2 seem to be selective for β-amyloid toxicity, as ER stress responses to thapsigargin or tunicamycin inTRPM2^−/−neurons was identical to that of wild-type neurons. Moreover, reduced microglial activation was observed inTRPM2^−/−/APP/PS1 hippocampus compared with APP/PS1 mice. In addition, age-dependent spatial memory deficits in APP/PS1 mice were reversed inTRPM2^−/−/APP/PS1 mice. These results reveal the importance of TRPM2 for β-amyloid neuronal toxicity, suggesting that TRPM2 activity could be potentially targeted to improve outcomes in Alzheimer's disease.SIGNIFICANCE STATEMENTTransient receptor potential melastatin 2 (TRPM2) is an oxidative stress sensing calcium-permeable channel that is thought to contribute to calcium dysregulation associated with neurodegenerative diseases, including Alzheimer's disease. Here we show that oligomeric β-amyloid, the toxic peptide in Alzheimer's disease, facilitates TRPM2 channel activation. In mice designed to model Alzheimer's disease, genetic elimination of TRPM2 normalized deficits in synaptic markers in aged mice. Moreover, the absence of TRPM2 improved age-dependent spatial memory deficits observed in Alzheimer's mice. Our results reveal the importance of TRPM2 for neuronal toxicity and memory impairments in an Alzheimer's mouse model and suggest that TRPM2 could be targeted for the development of therapeutic agents effective in the treatment of dementia.

Transient receptor potential melastatin 2 (TRPM2) is a calcium (Ca²⁺)-permeable non-selective cation channel belonging to the TRP ion channel family. Oxidative stress-induced TRPM2 activation provokes aberrant intracellular Ca²⁺ accumulation and cell death in a variety of cell types, including neurons. Aberrant TRPM2 function has been implicated in several neurological disorders including ischemia/stroke, Alzheimer's disease, neuropathic pain, Parkinson's disease and bipolar disorder. In addition to research identifying a role for TRPM2 in disease, progress has been made in the identification of physiological functions of TRPM2 in the brain, including recent evidence that TRPM2 is necessary for the induction of N-methyl-D-aspartate (NMDA) receptor-dependent long-term depression, an important form of synaptic plasticity at glutamate synapses. Here, we summarize recent evidence on the role of TRPM2 in the central nervous system (CNS) in health and disease and discuss the potential therapeutic implications of targeting TRPM2. Collectively, these studies suggest that TRPM2 represents a prospective novel therapeutic target for neurological disorders.

Pannexin‐1 (Panx1) is a large pore membrane channel with unique conduction properties ranging from non‐selective ion permeability to the extracellular release of signalling molecules. The release of ATP by Panx1 has been particularly well‐characterized with implications in purine signalling across a variety of biological contexts. Panx1 activity is also important in inflammasome formation and the secretion of pro‐inflammatory molecules such as interleukin‐1β. Within the central nervous system (CNS), Panx1 is expressed on both neurons and glia, and is thought to mediate crosstalk between these cells. A growing body of literature now supports the pathological activity of Panx1 in contributing to disease processes including seizure, stroke, migraine headache and chronic pain. Emerging evidence also reveals a physiological function of Panx1 in regulating neural stem cell survival, neuronal maturation and synaptic plasticity, with possible relevance to normal cognitive functioning. The aim of this review is to summarize the current evidence regarding the roles of Panx1 in the CNS, with emphasis on how putative signalling properties and activation mechanisms of this channel contribute to various physiological and pathophysiological processes. image

Pannexin-1 (Panx1) is a large-pore ion and solute permeable channel highly expressed in the nervous system, where it subserves diverse processes, including neurite outgrowth, dendritic spine formation, and N-methyl D-aspartate (NMDA) receptor (NMDAR)-dependent plasticity. Moreover, Panx1 dysregulation contributes to neurological disorders, including neuropathic pain, epilepsy, and excitotoxicity. Despite progress in understanding physiological and pathological functions of Panx1, the mechanisms that regulate its activity, including its ion and solute permeability, remain poorly understood. In this study, we identify endoplasmic reticulum (ER)-resident stromal interaction molecules (STIM1/2), which are Ca ²⁺ sensors that communicate events within the ER to plasma membrane channels, as binding and signaling partners of Panx1. We demonstrate that Panx1 is activated to its large-pore configuration in response to stimuli that recruit STIM1/2 and map the interaction interface to a hydrophobic region within the N terminus of Panx1. We further characterize a Panx1 N terminus–recognizing antibody as a function-blocking tool able to prevent large-pore Panx1 activation by STIM1/2. Using either the function-blocking antibody or re-expression of Panx1 deletion mutants in Panx1 knockout (KO) neurons, we show that STIM recruitment couples Ca ²⁺ entry via NMDARs to Panx1 activation, thereby identifying a model of NMDAR-STIM-Panx1 signaling in neurons. Our study highlights a previously unrecognized and important role of the Panx1 N terminus in regulating channel activation and membrane localization. Considering past work demonstrating an intimate functional relation between NMDARs and Panx1, our study opens avenues for understanding activation modality and context-specific functions of Panx1, including functions linked to diverse STIM-regulated cellular responses.