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

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 character-ized 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, learn-ing 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 ram-ifications, 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. Interest-ingly, 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 move-ments and pain perception, but little effect on hippocampal learning and memory.(c) 2023 IBRO. Published by Elsevier Ltd. All rights reserved.

Automated summary

ITPR1 is an important intracellular Ca2+ release channel involved in fundamental cellular functions. Although mutations in ITPR1 are associated with disease, most of the characterized mutations so far are loss of function. Dysregulation of ITPR1 function by interacting proteins has been implicated in ataxia, memory impairments, Alzheimer's disease progression, and chronic pain. However, direct evidence for the role of ITPR1 gain-of-function (GOF) mutations in disease is lacking. This study used a mouse model expressing a GOF mutation in the ITPR1 gating domain and found that it significantly affected motor movements and pain perception, but had little effect on hippocampal learning and memory.