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

Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca release channel are associated with human diseases. In this report, we investigated the functionality of three neuropathy-associated missense mutations in IPR3 (V615M, T1424M, and R2524C). The mutants only exhibited function when highly over-expressed compared to endogenous hIPR3. All variants resulted in elevated basal cytosolic Ca levels, decreased endoplasmic reticulum Ca store content, and constitutive store-operated Ca entry in the absence of any stimuli, consistent with a leaky IPR 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 IPR3 function. In addition, these mutations exhibit a novel phenotype manifested as a constitutively open channel, which inappropriately gates SOCE in the absence of stimulation.