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TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice
Sanjeev K Gotru1, Wenchun Chen1, Peter Kraft1
1From the Institute of Experimental Biomedicine, University Hospital of Würzburg (S.K.G., W.C., I.C.B., K.W., S.S., B.N., A.B.), Rudolf Virchow Center (S.K.G., W.C., I.C.B., K.W., S.S., B.N., A.B.), and Institute of Clinical Epidemiology and Biometry, Comprehensive Heart Failure Center (P.K.), University of Würzburg, Germany; Department of Hepatology (H.M.H.) and Department of Neurology (P.K., G.S.), University Hospital of Würzburg, Germany; Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig Maximilian University of Munich, Germany (S.Z., V.C., T.G.); Department of Immunology and Microbiology, University of Colorado, Denver (D.R., A.-L.P., C.S.); National Jewish Health, Denver, CO (D.R., A.-L.P., C.S.); Department of Molecular and Cellular Physiology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan (M.M.); Leibniz-Institut für Analytische Wissenschaften-ISAS-e.V., Dortmund, Germany (R.P.Z.); School of Biosciences, College of Life and Environmental Sciences, University of Birmingham, United Kingdom (P.J.N., M.G.T.); and Department of Bioinformatics, Functional Genomics and Systems Biology Group, University of Würzburg Biocenter, Germany (T.D.).
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 α-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 ) causes a marked signaling defect in platelets. Trpm7 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 γ2 and β3 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 mice from acute ischemic disease without developing intracranial hemorrhage indicates that TRPM7 kinase might be a promising antithrombotic target.
Insights
The TRPM7 kinase is crucial for platelet signaling, regulating calcium mobilization and aggregation. Inhibiting TRPM7 kinase may offer a new strategy for preventing arterial thrombosis and ischemic stroke.
Area of Science:
- Biochemistry
- Molecular Biology
- Cardiovascular Research
Background:
- TRPM7 (transient receptor potential cation channel, subfamily M, member 7) is a bifunctional protein with both channel and kinase activity.
- The specific physiological role of the TRPM7 kinase domain remains largely uncharacterized.
- Platelets play a critical role in hemostasis and thrombosis.
Purpose of the Study:
- To investigate the physiological role of the TRPM7 kinase domain in platelet function.
- To determine the impact of TRPM7 kinase activity on calcium signaling and platelet activation.
- To evaluate the therapeutic potential of targeting TRPM7 kinase in thrombotic diseases.
Main Methods:
- Generated mice with a point mutation in the TRPM7 kinase domain (Trpm7(km/km)).
- Analyzed platelet function, including PIP2 metabolism, calcium mobilization, and phosphorylation of key signaling proteins (Syk, PLCγ2, PLCβ3).
- Assessed store-operated calcium entry (SOCE) and platelet aggregation under flow conditions.
- Evaluated the in vivo efficacy of TRPM7 kinase inhibition in a mouse model of arterial thrombosis and ischemic stroke.
Main Results:
- Trpm7(km/km) platelets exhibited impaired PIP2 metabolism and reduced Ca2+ mobilization upon stimulation of major platelet receptors.
- Defective phosphorylation of Syk, PLCγ2, and PLCβ3 was observed in mutant platelets.
- Store-operated Ca2+ entry was significantly impaired in Trpm7(km/km) platelets.
- Mutant mice showed reduced platelet aggregate formation under flow and were protected from arterial thrombosis and ischemic stroke.
Conclusions:
- TRPM7 kinase is a key regulator of phospholipase C signaling and store-operated Ca2+ entry in platelets.
- TRPM7 kinase activity is essential for normal platelet activation and thrombus formation.
- TRPM7 kinase represents a promising therapeutic target for antithrombotic strategies, offering protection against ischemic events without increasing hemorrhage risk.
