Abstract
Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer’s disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy.
Highlights
We have recently shown that synaptic loss in Alzheimer’s disease (AD) might be caused by dysfunction in fine-tuning mechanism—store-operated calcium entry in hippocampal neurons [5,6,7,8,9,10]
STIM2 was initially described as a protein that regulates store-operated calcium entry in non-excitable cells; later on, it has been shown that it plays a major role in spine stabilization and regulates Neuronal store-operated calcium entry (nSOCE) in neurons [6]
Despite the beneficial effects of STIM2 protein expression for the stabilization of mushroom spines and nSOCE support in hippocampal neurons, STIM2 should not be taken as a lead cellular target for drug design due to the presence of preSTIM2 isoforms that regulate the activity of the ORAI channel in the store-independent manner as well as
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. When switching to clinical investigation, compounds developed via a historically standard pharmacological approach usually show either many crossspecificities and toxicities or the absence of therapeutic effects. This approach is time and cost consuming. We concentrate the review on perspectives to develop specific nSOC modulators based on the available 3D structures of TRPC6, ORAI2, and STIM2. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD, preventing therapy
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