title: Store-Operated Calcium Channel Complex in Postsynaptic Spines: A New Therapeutic Target for Alzheimer's Disease Treatment.
abstract: Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in aging and Alzheimer's disease (AD). The stability of mushroom spines depends on stromal interaction molecule 2 (STIM2)-mediated neuronal-store-operated Ca2+influx (nSOC) pathway, which is compromised in AD mouse models, in aging neurons, and in sporadic AD patients. Here, we demonstrate that the Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 channels form a STIM2-regulated nSOC Ca2+channel complex in hippocampal mushroom spines. We further demonstrate that a known TRPC6 activator, hyperforin, and a novel nSOC positive modulator, NSN21778 (NSN), can stimulate activity of nSOC pathway in the spines and rescue mushroom spine loss in both presenilin and APP knock-in mouse models of AD. We further show that NSN rescues hippocampal long-term potentiation impairment in APP knock-in mouse model. We conclude that the STIM2-regulated TRPC6/Orai2 nSOC channel complex in dendritic mushroom spines is a new therapeutic target for the treatment of memory loss in aging and AD and that NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
  
  
  
  Mushroom dendritic spine structures are essential for memory storage and the loss of mushroom spines may explain memory defects in Alzheimer's disease (AD). This study demonstrated that Transient Receptor Potential Canonical 6 (TRPC6) and Orai2 form stromal interaction molecule 2 (STIM2)-regulated neuronal-store-operated Ca2+influx (nSOC) channel complex in hippocampal synapse and the resulting Ca2+influx is critical for long-term maintenance of mushroom spines in hippocampal neurons. A novel nSOC-positive modulator, NSN21778 (NSN), rescues mushroom spine loss and synaptic plasticity impairment in AD mice models. The TRPC6/Orai2 nSOC channel complex is a new therapeutic target and NSN is a potential candidate molecule for therapeutic intervention in brain aging and AD.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.|Department of Neurology and Institute of Neurology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
authors.forename: Suya
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Lili
authors.initials: L
authors.lastname: Wu
authors.affiliation: Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia.
authors.forename: Ekaterina
authors.identifier: 0000-0002-3644-6886
authors.initials: E
authors.lastname: Pchitskaya
authors.affiliation: Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia.
authors.forename: Olga
authors.identifier: 0000-0002-2384-0681
authors.initials: O
authors.lastname: Zakharova
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390.
authors.forename: Klementina
authors.initials: K
authors.lastname: Fon Tacer
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, Ilya.Bezprozvanny@UTSouthwestern.edu.|Laboratory of Molecular Neurodegeneration, St. Petersburg State Polytechnical University, St. Petersburg 195251, Russia.
authors.forename: Ilya
authors.initials: I
authors.lastname: Bezprozvanny
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D000818:Animals; D001921:Brain; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000008:administration & dosage*; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology*; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D000071741:ORAI2 Protein / Q000819:agonists / Q000378:metabolism*; D013569:Synapses / Q000187:drug effects; D055366:Synaptic Potentials / Q000187:drug effects / Q000502:physiology; D050052:TRPC Cation Channels / Q000819:agonists / Q000378:metabolism*; D000074287:TRPC6 Cation Channel
chemical_list: D002120:Calcium Channel Agonists; D000071741:ORAI2 Protein; C520431:Orai2 protein, mouse; D050052:TRPC Cation Channels; D000074287:TRPC6 Cation Channel; C492146:Trpc6 protein, mouse; D002118:Calcium
keywords: calcium; channels; dendrites; hippocampus; imaging; synapse