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Gotru, Sanjeev K.; Chen, Wenchun; Kraft, Peter; Becker, Isabelle C.; Wolf, Karen; Stritt, Simon; Zierler, Susanna; Hermanns, Heike M.; Rao, Deviyani; Perraud, Anne-Laure; Schmitz, Carsten; Zahedi, Rene P.; Noy, Peter J.; Tomlinson, Michael G.; Dandekar, Thomas; Matsushita, Masayuki; Chubanov, Vladimir; Gudermann, Thomas; Stoll, Guido; Nieswandt, Bernhard; Braun, Attila (2018): TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice. In: Arteriosclerosis Thrombosis and Vascular Biology, Vol. 38, No. 2: pp. 344-352


Objective: TRPM7 (transient receptor potential cation channel, subfamily M, member 7) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic alpha-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg2+ and Ca2+ permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. Approach and Results: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7(R/R)) causes a marked signaling defect in platelets. Trpm7(R/R) platelets showed an impaired PIP2 (phosphatidylinositol-4,5-bisphosphate) metabolism and consequently reduced Ca2+ mobilization in response to stimulation of the major platelet receptors GPVI (glycoprotein VI), CLEC-2 (C-type lectin-like receptor), and PAR (protease-activated receptor). Altered phosphorylation of Syk (spleen tyrosine kinase) and phospholipase C gamma 2 and beta 3 accounted for these global platelet activation defects. In addition, direct activation of STIM1 (stromal interaction molecule 1) with thapsigargin revealed a defective store-operated Ca2+ entry mechanism in the mutant platelets. These defects translated into an impaired platelet aggregate formation under flow and protection of the mice from arterial thrombosis and ischemic stroke in vivo. Conclusions: Our results identify TRPM7 kinase as a key modulator of phospholipase C signaling and store-operated Ca2+ entry in platelets. The protection of Trpm7(R/R) mice from acute ischemic disease without developing intracranial hemorrhage indicates that TRPM7 kinase might be a promising antithrombotic target.