Abstract：
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.
摘要：
肌醇1,4,5-三磷酸受体1型(ITPR1)是对许多基本细胞功能重要的细胞内Ca2+释放通道。与其关键的生理意义一致，ITPR1的突变与疾病相关。令人惊讶的是,迄今为止,几乎所有的疾病相关ITPR1突变都是功能丧失.尽管缺乏ITPR1功能获得（GOF）突变，由于ITPR1相互作用蛋白失调而增强的ITPR1功能被认为与共济失调有关，学习和记忆障碍，阿尔茨海默病（AD）进展，和慢性疼痛。然而,缺乏ITPR1GOF在疾病中作用的直接证据。为了确定ITPR1中的GOF本身是否具有病理后果，我们采用了一种新开发的小鼠模型，在通道的门控域中表达ITPR1突变，D2594K,这显著增加了通道对IP3激活的敏感性。行为研究表明，ITPR1-D2594K+/-突变小鼠表现出运动缺陷和肌肉力量降低。然而,与5xFADAD模型小鼠杂交时,ITPR1-D2594K+/-突变不会显著改变海马学习和记忆,也不会改变学习和记忆障碍.另一方面,与WT相比,ITPR1-D2594K+/-小鼠表现出对热和机械刺激的敏感性增加。有趣的是,R-卡维地洛治疗减弱了ITPR1-D2594K+/-小鼠中增强的热和机械伤害感受。因此，通道门控域中的ITPR1-D2594K+/-突变对运动运动和疼痛感知有显著影响，但对海马学习和记忆影响不大。
