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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 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]