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Ischemia induces regulator of G protein signaling 2 (RGS2) protein; N; N( z% E; L g. X; }: v
upregulation and enhances apoptosis in astrocytes6 {2 R0 y) Y5 V: U. k( Z
Mehari Endale,1* Sung Dae Kim,1* Whi Min Lee,1 Sangseop Kim,2 Kyoungho Suk,2 Jae Youl Cho,3
2 f6 g% J8 X+ H0 p) QHwa Jin Park,4 Yadav Wagley,5 Suk Kim,6 Jae-Wook Oh,5 and Man Hee Rhee10 b T# U/ D" M0 r1 |& ~, ^# `
) j6 Y. S0 c2 m
Endale M, Kim SD, Lee WM, Kim S, Suk K, Cho JY, Park HJ,5 m3 X# O4 m6 Q+ e8 c
Wagley Y, Kim S, Oh JW, Rhee MH. Ischemia induces regulator of G
, h" ?+ h8 r; q( _protein signaling 2 (RGS2) protein upregulation and enhances apoptosis
& u3 _% e' `0 }in astrocytes. Am J Physiol Cell Physiol 298: C611–C623, 2010. First5 _( V$ q4 v `" M5 c$ L, \
published December 23, 2009; doi:10.1152/ajpcell.00517.2008.—Regulator
+ G) b; f2 {/ J mof G protein signaling (RGS) family members, such as RGS2,
: U: T: j- S& G. o& E. \) Ginteract with G subunits of heterotrimeric G proteins, accelerating/ ~ w" x6 J( L' h
the rate of GTP hydrolysis and attenuating the intracellular signaling4 [9 ]0 n2 I- B+ g1 n
triggered by the G protein-coupled receptor-ligand interaction.' ~' D) h" j$ F: `0 H- E3 G' p1 ~
They are also reported to regulate G protein-effector interactions
: A, @6 e/ K- w# ~8 e( J/ sand form multiprotein signaling complexes. Ischemic stress-induced2 X4 w! y% q8 H( e# {; U
changes in RGS2 expression have been described in astrocytes,
6 n2 h; f P8 L& `1 }5 D3 D4 K, ?8 Kand these changes are associated with intracellular signaling
( j( S) X4 o. d. \6 B' c% N! xcascades, suggesting that RGS2 upregulation may be an important
) C5 J+ \1 L' o: c# vmechanism by which astrocytes may regulate RGS2 function in
/ z" n1 T! @5 e/ [# C. \( nresponse to physiological stress. However, information on the6 V$ s" u# y6 n- H
functional roles of stress-induced modulation of RGS2 protein. O% J# K0 a7 U g9 @1 ]# C8 h6 R
expression in astrocyte function is limited. We report the role of
; N" { w3 q$ e5 D3 j; ^1 Jischemic stress in RGS2 protein expression in rat C6 astrocytoma
2 i# \9 O7 X/ k4 ~+ |. I3 f9 l- Ocells and primary mouse astrocytes. A marked increase in RGS2
/ k2 D# ]7 `/ _occurred after ischemic stress induced by chemicals (sodium azide
4 d$ c( {6 G c: g; Kand 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real* A+ ^% [' `) G+ k
ischemia). RGS2 mRNA expression was markedly enhanced by 1
$ R5 C7 ? F8 ]0 \% k# X. O2 H$ Bh of exposure to chemical ischemia or 6 h of OGD followed by 2
1 B- d$ ?1 @0 k! d5 Oor 6 h of recovery, respectively. This enhanced expression in
: f% b9 y2 a4 i* gprimary astrocytes and C6 cells was restored to baseline levels5 k6 Z# y% \/ i
after 12 h of recovery from chemically induced ischemic stress or" M m, H; F7 B+ q' j" N5 j
4 – 6 h of recovery from OGD. RGS2 protein was also significantly
; k' M# |9 g$ S q/ I! Z. hexpressed at 12–24 h of recovery from ischemic insult. Ischemiainduced
1 P- I, f7 W! ORGS2 upregulation was associated with enhanced apoptosis.% d) _. w1 k$ L5 C9 e" `0 S
It significantly increased annexin V-positive cells, cleaved! Z z4 V1 f. |1 N/ M6 ~
caspase-3, and enhanced DNA ladder formation and cell cycle
: ]1 }" ~0 e, U$ parrest. However, a small interfering RNA (siRNA)-mediated RGS2
; `% t1 O! ]! o5 O% i7 aknockdown reversed the apoptotic cell death associated with ischemia-" {! Y* z/ P# F, p. R( f9 M
induced RGS2 upregulation. Upregulated RGS2 was significantly" q4 u( f9 x- c& x* H# @2 o
inhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin,
& P" e7 M) ]2 w- P7 Q/ Ua potent inhibitor of PKC, completely abrogated the increased
6 X; X( m, |+ \8 M/ U3 e! M7 NRGS2 expression. We also examine whether ischemia-induced
+ Q, b5 V# E/ p$ A$ G# l; X$ @2 GRGS2-mediated apoptosis is affected by siRNA-targeted endogenous* c0 e. K. n ?: |6 ?
PKC downregulation or its phosphorylation. Although' @( }; k7 @$ M: R/ I" U+ a8 d
RGS2 upregulation was not affected, siRNA transfection significantly
+ v5 i3 Z- f5 [suppressed endogenous PKC mRNA and protein expresexpressions.
' A y& }/ H$ R' bIschemia-induced PKC phosphorylation and caspase-3
7 U; a2 g: ]1 J6 F& l* b- qcleavage were dose dependently inhibited by PKC knockdown,
; O! q& B* p9 Q5 h. K6 s$ t5 |and this endogenous PKC suppression reversed ischemia-induced6 \1 X: V ^5 c$ S4 i6 a
annexin V-positive cells. This study suggests that ischemic stress/ R$ A, `$ c9 R1 O6 C; A* Q
increases RGS2 expression and that this condition contributes to' N* e# C. N; H- [1 l5 [ O! G1 \
enhanced apoptosis in C6 cells and primary astrocytes. The signaling2 M+ x) h. j3 ^- Y: Y+ c/ ^/ j
it follows may involve PKC and p38 MAPK pathways.5 b" v& I n6 B: O! t% p
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发表于 2011-8-24 05:41
