Schmitz Carsten, Brandao Katherine, Perraud Anne-Laure
Integrated Department of Immunology, University of Colorado Denver, Denver, CO, 80206, USA, National Jewish Health, 1400 Jackson Street, Denver, CO, 80206, USA.
Integrated Department of Immunology, University of Colorado Denver, Denver, CO, 80206, USA.
Magnes Res. 2014 Jan-Mar;27(1):9-15. doi: 10.1684/mrh.2014.0357.
Ion homeostasis dysregulations have severe effects on human health, impairing the effectiveness and appropriateness of major cellular events, including immune responses. The adverse effects of Mg(2+) deficiency on cellular physiology are well known and documented, but mechanistic insights into Mg(2+) sensitive signal transduction are still lacking. TRPM7 and its sister channel TRPM6 stand out as the only known fusions of an ion pore with a Ser/Thr kinase domain. Both channels are permeable to divalent cations and are central regulators of Mg(2+) homeostasis. One crucial aspect of TRPM7 function we have extensively studied is the relationship between its ion channel portion and its C-terminal Ser/Thr kinase domain. The modulation of ion channels by phosphorylation through exogenous kinases is common, however the covalent bound between the TRPM7 channel and its kinase suggests a novel kind of link between ion-entry and signal transduction events. Current knowledge supports a reciprocal "two-way street" model where TRPM7-kinase modulates ion transport function through Ser/Thr phosphorylation, and in turn, channel gating and ionic conditions in close proximity to the pore regulate TRPM7-kinase mediated signaling. We have shown that TRPM7 acts as a sensor of Mg(2+)-availability, adjusting key cellular functions such as the rate of cellular protein translation to the Mg(2+) nutritional status. Since molecular mechanisms controlling rates of protein translation are critical for cell growth and division in response to nutrient availability, this could have relevance for example for therapies targeted at molecules shaping the cancerous translational apparatus. In our quest to understand the biology of Mg(2+) in the context of immune responses, we found that TRPM7 associates with, and phosphorylates phospholipase C gamma 2 (PLCγ2), a pivotal molecule in the signaling pathway following B-cell receptor (BCR) activation. This contributes to the Mg(2+)-dependent modulation of the Ca(2+) response elicited by BCR ligation, and provides the first molecular pathway underlying the Mg(2+)-sensitivity of immune responses. Expanding our knowledge about the modulation of immunoreceptor signaling in response to Mg(2+) availability could allow for the development of unexplored strategies for therapeutic intervention in autoimmune diseases, immunodeficiencies, and lymphoma.
离子稳态失调对人类健康有严重影响，会损害包括免疫反应在内的主要细胞活动的有效性和适当性。镁离子（Mg(2+)）缺乏对细胞生理的不利影响是众所周知且有文献记载的，但对Mg(2+)敏感信号转导的机制仍缺乏深入了解。瞬时受体电位通道M7（TRPM7）及其姊妹通道瞬时受体电位通道M6（TRPM6）是唯一已知的离子孔与丝氨酸/苏氨酸激酶结构域融合的通道。这两种通道都对二价阳离子具有通透性，并且是Mg(2+)稳态的核心调节因子。我们广泛研究的TRPM7功能的一个关键方面是其离子通道部分与其C末端丝氨酸/苏氨酸激酶结构域之间的关系。通过外源激酶磷酸化来调节离子通道是常见的，然而TRPM7通道与其激酶之间的共价结合表明离子进入与信号转导事件之间存在一种新型联系。目前的知识支持一种相互的“双向”模型，即TRPM7激酶通过丝氨酸/苏氨酸磷酸化调节离子转运功能，反过来，靠近孔的通道门控和离子条件调节TRPM7激酶介导的信号传导。我们已经表明，TRPM7作为Mg(2+)可用性的传感器，将关键的细胞功能（如细胞蛋白质翻译速率）调整到Mg(2+)营养状态。由于控制蛋白质翻译速率的分子机制对于细胞生长和对营养可用性的反应中的细胞分裂至关重要，这可能例如与针对塑造癌性翻译装置的分子的治疗方法相关。在我们探索免疫反应背景下Mg(2+)生物学的过程中，我们发现TRPM7与磷脂酶Cγ2（PLCγ2）结合并使其磷酸化，PLCγ2是B细胞受体（BCR）激活后信号通路中的关键分子。这有助于对BCR连接引发的Ca(2+)反应进行Mg(2+)依赖性调节，并提供了免疫反应Mg(2+)敏感性的首个分子途径。扩展我们对免疫受体信号转导响应Mg(2+)可用性调节的认识，可能有助于开发针对自身免疫性疾病、免疫缺陷和淋巴瘤的未探索的治疗干预策略。
