Regulation of TRPM7 Channels

项目总结 过度的TRPM7通道活性与神经细胞死亡、癌细胞转移以及我们的 初步数据将证明，高血压肥厚/心脏中心脏纤维化的发展 故障小鼠模型。总体而言，这些发现强调了TRPM7在急性髓细胞白血病的病理过程中的关键作用。 多种疾病，使经络成为治疗干预的有吸引力的目标。然而，具体的 体内控制TRPM7活性的机制尚不清楚。我们已经有了一个重要的发现 我们的初步数据表明，TRPM7与CNNM蛋白(CNNM1-4)结合，具有调节功能 通道的子单元。我们进一步证明，PTP4A磷酸酶激活依赖于CNNM的TRPM7 举止。TRPM7是第一个被发现的具有激活域的离子通道，其功能很差 明白了。我们最近报道了一项发现，该通道的自动磷酸化起着决定性作用 控制TRPM7蛋白表达的稳定性和该通道在细胞内的定位。我们假设 PTP4A磷酸酶、CNNMs和通道磷酸化协同作用调节TRPM7。在 多重等电点建议，我们提出了三个具体的目的来阐明控制的分子机制 TRPM7渠道，长期目标是了解渠道如何在 心脏纤维化。在具体目标1中，我们将使用电生理学、成像和生化方法来 阐明CNNMs和PTP4A对TRPM7的调控。在具体目标2中，我们将应用分析质量 光谱、生化和成像方法，以了解通道的磷酸化如何 调节TRPM7蛋白的表达及其细胞定位。在具体目标3中，我们将调查 控制心肌纤维化时经络病理刺激的特定机制(S)。有一个 迫切需要治疗中风、癌症和心脏病的新疗法，这些疾病导致数百万人死亡或严重残疾 每年都有个人。我们的调查结果将产生重大影响，因为 该通道的调控机制可能导致临床上阻断TRPM7‘S的新方法 在这些毁灭性疾病中的病理行为。

PROJECT SUMMARY Excessive TRPM7 channel activity is linked to neuronal cell death, cancer cell metastasis, and as our preliminary data will demonstrate, the development of cardiac fibrosis in a hypertensive hypertrophy/heart failure mouse model. Collectively, these findings underscore a critical role for TRPM7 in the pathology of a multitude of diseases, making channel an attractive target for therapeutic intervention. However, the specific mechanisms controlling TRPM7 activity in vivo remain unknown. We have made the critical discovery that TRPM7 binds to CNNM proteins (CNNM1-4), which our preliminary data indicate function as regulatory subunits of the channel. We further show that PTP4A phosphatases activate TRPM7 in a CNNM-dependent manner. TRPM7 is the first identified ion channel to possess a kinase domain, the function of which is poorly understood. We recently reported the discovery that auto-phosphorylation of the channel plays a decisive role in controlling the stability of TRPM7 protein expression and the channel's localization in cells. We hypothesize that PTP4A phosphatases, CNNMs, and channel phosphorylation operate in concert to regulate TRPM7. In the multi-PI proposal, we propose three specific aims to elucidate the molecular mechanisms controlling the TRPM7 channel with the long-term goal of understanding how the channel becomes upregulated during cardiac fibrosis. In specific aim 1, we will employ electrophysiology, imaging, and biochemical approaches to elucidate the regulation of TRPM7 by CNNMs and PTP4As. In specific aim 2, we will apply analytical mass spectrometry, biochemical, and imaging approaches to understand how phosphorylation of the channel regulates TRPM7 protein expression and its cellular localization. In specific aim 3, we will investigate the specific mechanism(s) controlling pathological stimulation of the channel during cardiac fibrosis. There is an urgent need for new treatments for stroke, cancer, and heart disease, which kill or severely disable millions of individuals each year. Results from our investigation will have a significant impact by uncovering the mechanisms controlling the channel, which may lead to novel clinical approaches for blocking TRPM7's pathological actions in these devastating diseases.