Department of Biochemistry and Signal Transduction, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246, Hamburg, Germany.
German Mouse Clinic, Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, 85764, Neuherberg, Germany.
Neurosci Lett. 2020 Sep 14;735:135206. doi: 10.1016/j.neulet.2020.135206. Epub 2020 Jun 25.
Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is the neuronal isoform of ITPKs and exhibits both actin bundling and InsPkinase activity. In addition to neurons, ITPKA is ectopically expressed in tumor cells, where its oncogenic activity increases tumor cell malignancy. In order to analyze the physiological relevance of ITPKA, here we performed a broad phenotypic screening of itpka deficient mice. Our data show that among the neurobehavioral tests analyzed, itpka deficient mice reacted faster to a hotplate, prepulse inhibition was impaired and the accelerating rotarod test showed decreased latency of itpka deficient mice to fall. These data indicate that ITPKA is involved in the regulation of nociceptive pathways, sensorimotor gating and motor learning. Analysis of extracerebral functions in control and itpka deficient mice revealed significantly reduced glucose, lactate, and triglyceride plasma concentrations in itpka deficient mice. Based on this finding, expression of ITPKA was analyzed in extracerebral tissues and the highest level was found in the small intestine. However, functional studies on CaCo-2 control and ITPKA depleted cells showed that glucose, as well as triglyceride uptake, were not significantly different between the cell lines. Altogether, these data show that ITPKA exhibits distinct functions in the central nervous system and reveal an involvement of ITPKA in energy metabolism.
肌醇-1,4,5-三磷酸 3-激酶-A（ITPKA）是 ITPKs 的神经元同工型，具有肌动蛋白成束和 InsP 激酶活性。除神经元外，ITPKA 在肿瘤细胞中也异位表达，其致癌活性增加了肿瘤细胞的恶性程度。为了分析 ITPKA 的生理相关性，我们在这里对 itpka 缺陷小鼠进行了广泛的表型筛选。我们的数据表明，在分析的神经行为测试中，itpka 缺陷小鼠对热板的反应更快，前脉冲抑制受损，加速旋转棒测试显示 itpka 缺陷小鼠跌倒的潜伏期降低。这些数据表明 ITPKA 参与了痛觉通路、感觉运动门控和运动学习的调节。在对照和 itpka 缺陷小鼠中分析脑外功能时，发现 itpka 缺陷小鼠的血浆葡萄糖、乳酸和甘油三酯浓度显著降低。基于这一发现，分析了脑外组织中 ITPKA 的表达，发现其在小肠中的表达水平最高。然而，对 CaCo-2 对照和 ITPKA 耗尽细胞的功能研究表明，葡萄糖以及甘油三酯的摄取在细胞系之间没有显著差异。总之，这些数据表明 ITPKA 在中枢神经系统中表现出明显不同的功能，并揭示了 ITPKA 参与能量代谢。
