The channel-kinase TRPM7, revealing the untold story of Mg(2+) in cellular signaling.

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 Mg2+ deficiency on cellular physiology are well known and documented, but mechanistic insights into Mg2+ 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 Mg2+ 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 Mg2+-availability, adjusting key cellular functions such as the rate of cellular protein translation to the Mg2+ 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 Mg2+ 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 Mg2+-dependent modulation of the Ca2+ response elicited by BCR ligation, and provides the first molecular pathway underlying the Mg2+-sensitivity of immune responses. Expanding our knowledge about the modulation of immunoreceptor signaling in response to Mg2+ availability could allow for the development of unexplored strategies for therapeutic intervention in autoimmune diseases, immunodeficiencies, and lymphoma.