title: Both Orai1 and TRPC1 are Involved in Excessive Store-Operated Calcium Entry in Striatal Neurons Expressing Mutant Huntingtin Exon 1.
abstract: It has been previously reported that N-terminus of mutant huntingtin (product of the 1st exon) is sufficient to cause a Huntington's disease (HD) pathological phenotype. In view of recent data suggesting that improper regulation of store-operated calcium (SOC) channels is involved in neurodegenerative processes, we investigated influence of expression of the mutant huntingtin N-terminal fragment (Htt138Q-1exon) on SOC entry (SOCE) in mouse neuroblastoma cells (Neuro-2a) and in primary culture of medium spiny neurons (MSNs) isolated from mice. The results show that SOCE in these cells is enhanced upon lentiviral expression of the Htt138Q-1exon. Moreover, we demonstrated that RNAi-mediated knockdown of TRPC1, Orai1, or STIM1 proteins leads to dramatic reduction of abnormal SOCE in both Neuro-2a and MSNs, expressing Htt138Q-1exon. Thus, we concluded that abnormal SOCE in these cells is maintained by both TRPC1- and Orai1-containing channels and required STIM1 for its activation. Furthermore, EVP4593 compound previously tested as a potential anti-HD drug in a Drosophila screening system has proved to be capable of reducing SOCE to the normal level in MSNs expressing the Htt138Q-1exon.
authors.affiliation: Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Vigont
authors.affiliation: Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Yulia
authors.initials: Y
authors.lastname: Kolobkova
authors.affiliation: Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Anton
authors.initials: A
authors.lastname: Skopin
authors.affiliation: Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Zimina
authors.affiliation: Laboratory of Intracellular Membrane Dynamics, Flow Cytometry and Sorting Group, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Valery
authors.initials: V
authors.lastname: Zenin
authors.affiliation: Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Lyuba
authors.initials: L
authors.lastname: Glushankova
authors.affiliation: Laboratory of Ionic Channels of Cell Membranes, Institute of Cytology, Russian Academy of Sciences St. Petersburg, Russia.
authors.forename: Elena
authors.initials: E
authors.lastname: Kaznacheyeva
keywords: Huntington's disease; Orai1; STIM1; TRPC1; ionic channels; neurodegeneration; store-operated calcium entry