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10.1074/jbc.M112.411272

http://scihub22266oqcxt.onion/10.1074/jbc.M112.411272
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suck abstract from ncbi


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pmid23625915
      J+Biol+Chem 2013 ; 288 (23 ): 17030-17041
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  • Store-operated Ca2+ entry (SOCE) induced by protease-activated receptor-1 mediates STIM1 protein phosphorylation to inhibit SOCE in endothelial cells through AMP-activated protein kinase and p38? mitogen-activated protein kinase #MMPMID23625915
  • Sundivakkam PC ; Natarajan V ; Malik AB ; Tiruppathi C
  • J Biol Chem 2013[Jun]; 288 (23 ): 17030-17041 PMID23625915 show ga
  • The Ca(2+) sensor STIM1 is crucial for activation of store-operated Ca(2+) entry (SOCE) through transient receptor potential canonical and Orai channels. STIM1 phosphorylation serves as an "off switch" for SOCE. However, the signaling pathway for STIM1 phosphorylation is unknown. Here, we show that SOCE activates AMP-activated protein kinase (AMPK); its effector p38? mitogen-activated protein kinase (p38? MAPK) phosphorylates STIM1, thus inhibiting SOCE in human lung microvascular endothelial cells. Activation of AMPK using 5-aminoimidazole-4-carboxamide-1-?-d-ribofuranoside (AICAR) resulted in STIM1 phosphorylation on serine residues and prevented protease-activated receptor-1 (PAR-1)-induced Ca(2+) entry. Furthermore, AICAR pretreatment blocked PAR-1-induced increase in the permeability of mouse lung microvessels. Activation of SOCE with thrombin caused phosphorylation of isoform ?1 but not ?2 of the AMPK catalytic subunit. Moreover, knockdown of AMPK?1 augmented SOCE induced by thrombin. Interestingly, SB203580, a selective inhibitor of p38 MAPK, blocked STIM1 phosphorylation and led to sustained STIM1-puncta formation and Ca(2+) entry. Of the three p38 MAPK isoforms expressed in endothelial cells, p38? knockdown prevented PAR-1-mediated STIM1 phosphorylation and potentiated SOCE. In addition, inhibition of the SOCE downstream target CaM kinase kinase ? (CaMKK?) or knockdown of AMPK?1 suppressed PAR-1-mediated phosphorylation of p38? and hence STIM1. Thus, our findings demonstrate that SOCE activates CaMKK?-AMPK?1-p38? MAPK signaling to phosphorylate STIM1, thereby suppressing endothelial SOCE and permeability responses.
  • |AMP-Activated Protein Kinases/genetics/*metabolism [MESH]
  • |Aminoimidazole Carboxamide/analogs & derivatives/pharmacology [MESH]
  • |Animals [MESH]
  • |Calcium Channels [MESH]
  • |Calcium-Calmodulin-Dependent Protein Kinase Kinase/genetics/metabolism [MESH]
  • |Calcium/*metabolism [MESH]
  • |Capillary Permeability/drug effects/physiology [MESH]
  • |Cells, Cultured [MESH]
  • |Endothelial Cells/cytology/*metabolism [MESH]
  • |Gene Knockdown Techniques [MESH]
  • |Humans [MESH]
  • |Hypoglycemic Agents/pharmacology [MESH]
  • |Lung/blood supply/metabolism [MESH]
  • |Membrane Glycoproteins/genetics/*metabolism [MESH]
  • |Membrane Proteins/genetics/*metabolism [MESH]
  • |Mitogen-Activated Protein Kinase 11/genetics/*metabolism [MESH]
  • |Neoplasm Proteins/genetics/*metabolism [MESH]
  • |Phosphorylation/drug effects/physiology [MESH]
  • |Receptor, PAR-1/genetics/*metabolism [MESH]
  • |Ribonucleotides/pharmacology [MESH]


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