Regulation of TRPM7 Channels

TRPM7通道活性过高与神经细胞死亡、癌细胞转移以及我们的初步数据将证明，在高血压肥厚/心力衰竭小鼠模型中心脏纤维化的发展有关。总而言之，这些发现强调了TRPM7在多种疾病的病理中的关键作用，使通道成为治疗干预的一个有吸引力的目标。然而，体内控制TRPM7活性的具体机制仍不清楚。我们已经取得了关键的发现，TRPM7与CNNM蛋白(CNNM1-4)结合，我们的初步数据表明，CNNM蛋白作为通道的调节亚单位发挥功能。我们进一步表明，PTP4A磷酸酶以CNNM依赖的方式激活TRPM7。TRPM7是第一个被发现具有激活域的离子通道，其功能尚不清楚。我们最近发现，该通道的自动磷酸化在控制TRPM7蛋白表达的稳定性和该通道在细胞中的定位方面起着决定性的作用。我们假设PTP4A磷酸酶、CNNMs和通道磷酸化协同作用来调节TRPM7。在多PI方案中，我们提出了三个具体目标来阐明控制TRPM7通道的分子机制，长期目标是了解该通道在心脏纤维化过程中是如何上调的。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，我们将应用分析质谱学、生化和成像方法来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，我们将研究在心肌纤维化过程中控制经络病理性刺激的特定机制(S)。人们迫切需要治疗中风、癌症和心脏病的新疗法，这些疾病每年导致数百万人死亡或严重致残。我们的研究结果将对揭示该通道的控制机制产生重大影响，这可能导致临床上阻断TRPM7‘S在这些毁灭性疾病中的病理作用的新方法。

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.