Regulation of TRPM7 Channels

项目摘要 过度的TRPM 7通道活性与神经元细胞死亡、癌细胞转移有关， 初步数据将证明，高血压性肥大/心脏中心脏纤维化的发展 失败小鼠模型。总的来说，这些发现强调了TRPM 7在肿瘤病理学中的关键作用。 许多疾病，使通道成为治疗干预的有吸引力的目标。但具体 体内控制TRPM 7活性的机制仍然未知。我们有了一个重要发现， TRPM 7与CNNM蛋白（CNNM 1 -4）结合，我们的初步数据表明，CNNM蛋白具有调节功能。 通道的子单元。我们进一步表明，PTP 4A磷酸酶激活TRPM 7在CNNM依赖性 方式TRPM 7是第一个被鉴定的具有激酶结构域的离子通道，其功能很差 明白我们最近报道发现，通道的自磷酸化起着决定性作用 控制TRPM 7蛋白表达的稳定性和通道在细胞中的定位。我们假设 PTP 4A磷酸酶、CNNM和通道磷酸化协同作用调节TRPM 7。在 多PI的建议，我们提出了三个具体的目标，以阐明控制的分子机制， TRPM 7通道的长期目标是了解该通道如何在治疗过程中上调。 心脏纤维化在具体目标1中，我们将采用电生理学、成像和生物化学方法， 阐明CNNM和PTP 4A对TRPM 7的调节。在具体目标2中，我们将应用分析质量 光谱，生物化学和成像方法，以了解如何磷酸化的通道 调节TRPM 7蛋白表达及其细胞定位。在具体目标3中，我们将研究 在心脏纤维化期间控制通道的病理刺激的特定机制。有一个 迫切需要新的治疗中风，癌症和心脏病，这些疾病导致数百万人死亡或严重残疾。 个人每年。我们的调查结果将产生重大影响， 控制通道的机制，这可能导致阻断TRPM 7的新的临床方法。 在这些毁灭性疾病中的病理作用。

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.