Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca²⁺ channels and activation of store-operated Ca²⁺ entry.

ABSTRACT: 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 functionality of three neuropathy-associated missense mutations in IP₃R3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIP₃R3. 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 fu

SUBMITTER: Terry LE 

PROVIDER: S-EPMC9700043 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature