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Information × Registration Number 0220U103719, 0118U007345 , R & D reports Title NCS protein signaling in CNS neurons in norm and pathology. popup.stage_title Head Bilan Pavlo V., Доктор біологічних наук Registration Date 16-11-2020 Organization Bogomolets Institute of Physiology of the National Academy of Sciences of Ukraine popup.description2 Primary dystonia is a neurological movement disorder syndrome in which sustained or repetitive muscle contractions result in twisting and repetitive movements or abnormal painful postures. The brain of patients with primary dystonia contains no overt abnormalities. At the same time, anatomical and functional imaging demonstrates different abnormalities in many brain regions including the cerebral cortex, striatum, cerebellum, thalamus, midbrain/brain- stem as well as the hippocampus that may contribute to manifestation of dystonia symptoms. The recent genetic study of patients with DYT2 dystonia revealed three point mutations in HPCA, a gene encoding a neuronal calcium sensor (NCS) protein, hippocalcin (HPCA). HPCA contains three EF-hand do- mains capable of binding Ca2+. The binding results in a Ca2+-myristoyl switch, a Ca2+-dependent conformation change leading to protrusion of its myristoyl-containing N-terminal region out of a hydrophobic pocket of the molecule. This allows HPCA to translocate from the cytosol to the plasma membrane. It is established that this Ca2+-dependent translocation of HPCA leads to inhibition of cortical and hippocampal neurons by gating a slow afterhyperpolarization (sAHP) current. We have hypothesized that the DYT2 mutations perturb HPCA signaling and sAHP gating leading to increased neuronal excitability. We initially tested this hypothesis using HEK-293 cells transfected with wild- type HPCA (WT HPCA) and its DYT2 mutants. We showed that WT HPCA has a larger total Ca2+ buffer capacity than N75K mutant in a studied range of [Ca2+]i and its buffer capacity is relatively larger at the basal rather than higher levels of [Ca2+]i contrary to N75K mutants. The latter also indicates that WT HPCA affinity for Ca2+ is higher than one of its dystonic N75K mutant. Altogether, our data indicate that both Ca2+-myristoyl switch and translocation selectivity to certain membranes were not substantially affected by DYT2 mutations. At the same time, N  Product Description popup.authors Borisyuk Anna L Anna L. Hryshchenko Oleksiy V. Dovgan Olexandr V. Dromaretsky Andriy V. Kononenko Mykola I. Korohod Serhiy М. Krotov Volodymyr V. Saftenko Olena E. popup.nrat_date 2020-11-16 Close