Missense mutations in inositol 1,4,5-trisphosphate receptor type 3 result in leaky Ca(2+) channels and activation of store-operated Ca(2+) entry

Mutations in all subtypes of the inositol 1,4,5-trisphosphate receptor Ca(2+) release channel are associated with human diseases. In this report, we investigated the functionality 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 Ca(2+) levels, decreased endoplasmic reticulum Ca(2+) store content, and constitutive store-operated Ca(2+) entry in the absence of any stimuli, consistent with a leaky IP(3)R 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.