Journal
FRONTIERS IN PHARMACOLOGY
Volume 9, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2018.00696
Keywords
store-operated calcium channels; SOC; Huntington's disease; neurodegeneration; EVP4593; iPS cells; CRAC channels
Categories
Funding
- Russian Science Foundation [17-74-20068]
- Russian Foundation for Basic Research [17-54-80006 BRICS]
- Russian Federation
- Russian Science Foundation [17-74-20068] Funding Source: Russian Science Foundation
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Neurodegenerative pathologies are among the most serious and socially significant problems of modern medicine, along with cardiovascular and oncological diseases. Several attempts have been made to prevent neuronal death using novel drugs targeted to the cell calcium signaling machinery, but the lack of adequate models for screening markedly impairs the development of relevant drugs. A potential breakthrough in this field is offered by the models of hereditary neurodegenerative pathologies based on endogenous expression of mutant proteins in neurons differentiated from patientspecific induced pluripotent stem cells (iPSCs). Here, we study specific features of store-operated calcium entry (SOCE) using an iPSCs-based model of Huntington's disease (HD) and analyze the pharmacological effects of a specific drug targeted to the calcium channels. We show that SOCE in gamma aminobutyric acid-ergic striatal medium spiny neurons (GABA MSNs) was mediated by currents through at least two different channel groups, I-CRAC and I-SOC. Both of these groups were upregulated in HD neurons compared with the wild-type neurons. Thapsigargin-induced intracellular calcium store depletion in GABA MSNs resulted in predominant activation of either I-CRAC or I-SOC. The potential anti-HD drug EVP4593, which was previously shown to have neuroprotective activity in different HD models, affected both I-CRAC and I-SOC.
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