期刊
ISCIENCE
卷 25, 期 12, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.isci.2022.105523
关键词
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资金
- National Institutes of Health [NIH/DE0014756, F31 NIH/DE030670]
- Research Council of the KU Leuven [AKUL/19/34]
- FWO Scientific Research Network CaSign [W0.019.17N, W001422N]
- Foundation Flanders [G094522N]
Mutations in IP(3)R3 were found to result in decreased receptor function, leading to elevated cytosolic Ca2+ levels, decreased endoplasmic reticulum Ca2+ store content, and constitutively open channels in the absence of stimulation. These mutations exhibited different levels of channel activity.
Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca2+ release channel are associated with human diseases. In this report, we investigated the functionalty of three neuropathy-associated missense mutations in IP(3)R3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIP(3)R3. All variants resulted in elevated basal cytosolic Ca2+ levels, decreased endoplasmic reticulum Ca2+ store content, and constitutive store-operated Ca2+ entry in the absence of any stimuli, consistent with a leaky IP3R channel pore. These variants differed in channel function; when stably over-expressed the R2524C mutant was essentially dead, V615M was poorly functional, and T1424M exhibited activity greater than that of the corresponding wild-type following threshold stimulation. These results demonstrate that a common feature of these mutations is decreased IP(3)R3 function. In addition, these mutations exhibit a novel phenotype manifested as a constitutively open channel, which inappropriately gates SOCE in the absence of stimulation.
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