PMID- 37252113
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230531
IS  - 2297-055X (Print)
IS  - 2297-055X (Electronic)
IS  - 2297-055X (Linking)
VI  - 10
DP  - 2023
TI  - The NMDA receptor regulates integrin activation, ATP release and arterial 
      thrombosis through store-operated Ca(2+) entry in platelets.
PG  - 1171831
LID - 10.3389/fcvm.2023.1171831 [doi]
LID - 1171831
AB  - INTRODUCTION: Platelet activation and thrombus formation is crucial for 
      hemostasis, but also trigger arterial thrombosis. Calcium mobilization plays an 
      important role in platelet activation, because many cellular processes depend on 
      the level of intracellular Ca(2+) ([Ca(2+)](i)), such as integrin activation, 
      degranulation, cytoskeletal reorganization. Different modulators of Ca(2+) 
      signaling have been implied, such as STIM1, Orai1, CyPA, SGK1, etc. Also, the 
      N-methyl-D-aspartate receptor (NMDAR) was identified to contribute to Ca(2+) 
      signaling in platelets. However, the role of the NMDAR in thrombus formation is 
      not well defined. METHODS: In vitro and in vivo analysis of platelet-specific 
      NMDAR knock-out mice. RESULTS: In this study, we analyzed Grin1(fl/fl)-Pf4-Cre(+) 
      mice with a platelet-specific knock-out of the essential GluN1 subunit of the 
      NMDAR. We found reduced store-operated Ca(2+) entry (SOCE), but unaltered store 
      release in GluN1-deficient platelets. Defective SOCE resulted in reduced Src and 
      PKC substrate phosphorylation following stimulation of glycoprotein (GP)VI or the 
      thrombin receptor PAR4 followed by decreased integrin activation but unaltered 
      degranulation. Consequently, thrombus formation on collagen under flow conditions 
      was reduced ex vivo, and Grin1(fl/fl)-Pf4-Cre(+) mice were protected against 
      arterial thrombosis. Results from human platelets treated with the NMDAR 
      antagonist MK-801 revealed a crucial role of the NMDAR in integrin activation and 
      Ca(2+) homeostasis in human platelets as well. CONCLUSION: NMDAR signaling is 
      important for SOCE in platelets and contributes to platelet activation and 
      arterial thrombosis. Thus, the NMDAR represents a novel target for anti-platelet 
      therapy in cardiovascular disease (CVD).
CI  - (c) 2023 Reusswig, Yilmaz, Brechtenkamp, Kruger, Metz, Klocker, Lammert and Elvers.
FAU - Reusswig, Friedrich
AU  - Reusswig F
AD  - Department of Vascular- and Endovascular Surgery, University Hospital Dusseldorf, 
      Heinrich-Heine University, Dusseldorf, Germany.
FAU - Yilmaz, Munteha
AU  - Yilmaz M
AD  - Department of Vascular- and Endovascular Surgery, University Hospital Dusseldorf, 
      Heinrich-Heine University, Dusseldorf, Germany.
FAU - Brechtenkamp, Marius
AU  - Brechtenkamp M
AD  - Department of Vascular- and Endovascular Surgery, University Hospital Dusseldorf, 
      Heinrich-Heine University, Dusseldorf, Germany.
FAU - Krueger, Irena
AU  - Krueger I
AD  - Department of Vascular- and Endovascular Surgery, University Hospital Dusseldorf, 
      Heinrich-Heine University, Dusseldorf, Germany.
FAU - Metz, Lisa Maria
AU  - Metz LM
AD  - Department of Vascular- and Endovascular Surgery, University Hospital Dusseldorf, 
      Heinrich-Heine University, Dusseldorf, Germany.
FAU - Klocker, Nikolaj
AU  - Klocker N
AD  - Institute of Neural and Sensory Physiology, Medical Faculty and University 
      Hospital Dusseldorf, Heinrich-Heine University, Dusseldorf, Germany.
FAU - Lammert, Eckhard
AU  - Lammert E
AD  - Institute for Vascular and Islet Cell Biology, German Diabetes Center (DDZ), 
      Leibniz Center for Diabetes Research at Heinrich-Heine University, Dusseldorf, 
      Germany.
AD  - German Center for Diabetes Research (DZD e.V.), Helmholtz Zentrum Munchen, 
      Neuherberg, Germany.
AD  - Institute of Metabolic Physiology, Heinrich Heine University, Dusseldorf, 
      Germany.
FAU - Elvers, Margitta
AU  - Elvers M
AD  - Department of Vascular- and Endovascular Surgery, University Hospital Dusseldorf, 
      Heinrich-Heine University, Dusseldorf, Germany.
LA  - eng
PT  - Journal Article
DEP - 20230512
PL  - Switzerland
TA  - Front Cardiovasc Med
JT  - Frontiers in cardiovascular medicine
JID - 101653388
PMC - PMC10217778
OTO - NOTNLM
OT  - ATP
OT  - NMDAR
OT  - calcium
OT  - integrin
OT  - platelets
OT  - thrombosis
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2023/05/30 13:07
MHDA- 2023/05/30 13:08
PMCR- 2023/01/01
CRDT- 2023/05/30 11:49
PHST- 2023/02/22 00:00 [received]
PHST- 2023/04/27 00:00 [accepted]
PHST- 2023/05/30 13:08 [medline]
PHST- 2023/05/30 13:07 [pubmed]
PHST- 2023/05/30 11:49 [entrez]
PHST- 2023/01/01 00:00 [pmc-release]
AID - 10.3389/fcvm.2023.1171831 [doi]
PST - epublish
SO  - Front Cardiovasc Med. 2023 May 12;10:1171831. doi: 10.3389/fcvm.2023.1171831. 
      eCollection 2023.