Regulation of TRPM7 Channels

过度的 TRPM7 通道活性与神经细胞死亡、癌细胞转移有关，并且正如我们的初步数据将证明的那样，与高血压肥厚/心力衰竭小鼠模型中心脏纤维化的发展有关。总的来说，这些发现强调了 TRPM7 在多种疾病病理学中的关键作用，使通道成为治疗干预的有吸引力的目标。然而，体内控制TRPM7活性的具体机制仍不清楚。我们做出了关键的发现，即 TRPM7 与 CNNM 蛋白 (CNNM1-4) 结合，我们的初步数据表明其具有通道调节亚基的功能。我们进一步表明 PTP4A 磷酸酶以 CNNM 依赖性方式激活 TRPM7。 TRPM7 是第一个被识别的具有激酶结构域的离子通道，但其功能尚不清楚。我们最近报道了通道的自磷酸化在控制 TRPM7 蛋白表达的稳定性和通道在细胞中的定位中起着决定性作用的发现。我们假设 PTP4A 磷酸酶、CNNM 和通道磷酸化协同作用来调节 TRPM7。在多PI提案中，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如何上调。在具体目标 1 中，我们将采用电生理学、成像和生化方法来阐明 CNNM 和 PTP4As 对 TRPM7 的调节。在具体目标 2 中，我们将应用分析质谱、生化和成像方法来了解通道的磷酸化如何调节 TRPM7 蛋白表达及其细胞定位。在具体目标3中，我们将研究控制心脏纤维化过程中通道病理刺激的具体机制。中风、癌症和心脏病每年导致数百万人死亡或严重致残，因此迫切需要新的治疗方法。我们的研究结果将通过揭示控制该通道的机制产生重大影响，这可能会带来新的临床方法来阻断 TRPM7 在这些毁灭性疾病中的病理作用。

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.