A Gain-of-function Mutation in the Gating Domain of ITPR1 Impairs Motor Movement and Increases Thermal and Mechanical Sensitivity

Inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) is an intracellular Ca²⁺ release channel important for a number of fundamental cellular functions. Consistent with its critical physiological significance, mutations in ITPR1 are associated with disease. Surprisingly, nearly all the disease-associated ITPR1 mutations characterized to date are loss of function. Despite the paucity of ITPR1 gain-of-function (GOF) mutations, enhanced ITPR1 function as a result of dysregulation by ITPR1 interacting proteins is thought to be associated with ataxia, learning and memory impairments, Alzheimer's disease (AD) progression, and chronic pain. However, direct evidence for the role of ITPR1 GOF in disease is lacking. To determine whether GOF in ITPR1 itself has pathological ramifications, we employed a newly developed mouse model expressing an ITPR1 mutation in the gating domain of the channel, D2594K, that markedly increased the channel's sensitivity to activation by IP₃. Behavioral studies showed that the ITPR1-D2594K^+/- mutant mice displayed motor deficits and reduced muscle strength. However, the ITPR1-D2594K^+/- mutation did not significantly alter hippocampal learning and memory and did not change learning and memory impairments when crossed with the 5xFAD AD model mice. On the other hand, ITPR1-D2594K^+/- mice exhibited increased sensitivity to thermal and mechanical stimulation compared to WT. Interestingly, R-carvedilol treatment attenuated the enhanced thermal and mechanical nociception in ITPR1-D2594K^+/- mice. Thus, the ITPR1-D2594K^+/- mutation in the channel's gating domain has a marked impact on motor movements and pain perception, but little effect on hippocampal learning and memory.