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Ischemia induces regulator of G protein signaling 2 (RGS2) protein
4 c, N- m: e B% G# o lupregulation and enhances apoptosis in astrocytes9 Y$ m/ t+ g" E
Mehari Endale,1* Sung Dae Kim,1* Whi Min Lee,1 Sangseop Kim,2 Kyoungho Suk,2 Jae Youl Cho,3' n1 Z; W; N: |7 `0 Z7 m3 `1 A4 h
Hwa Jin Park,4 Yadav Wagley,5 Suk Kim,6 Jae-Wook Oh,5 and Man Hee Rhee14 R. @( g, v( I! l- J3 o
O, E2 ?2 l3 Y) a2 w; [- q9 ~
Endale M, Kim SD, Lee WM, Kim S, Suk K, Cho JY, Park HJ,
# ]# \& d9 O% W3 rWagley Y, Kim S, Oh JW, Rhee MH. Ischemia induces regulator of G
5 c6 H% Q+ H& l7 q5 bprotein signaling 2 (RGS2) protein upregulation and enhances apoptosis
3 P3 d. F$ o w. vin astrocytes. Am J Physiol Cell Physiol 298: C611–C623, 2010. First
9 N' Y8 n. I2 k0 u! h, apublished December 23, 2009; doi:10.1152/ajpcell.00517.2008.—Regulator
2 X: }5 B) {# C7 B$ pof G protein signaling (RGS) family members, such as RGS2,
: Q5 U/ R0 D4 |+ [+ finteract with G subunits of heterotrimeric G proteins, accelerating9 Z& b! Z6 Q( e- ~ a
the rate of GTP hydrolysis and attenuating the intracellular signaling2 ~; Y. O @ \* p
triggered by the G protein-coupled receptor-ligand interaction.
2 o5 ^" }! s% ^7 zThey are also reported to regulate G protein-effector interactions0 |: B2 r) d- ]; Y
and form multiprotein signaling complexes. Ischemic stress-induced
+ L T6 M6 a2 l1 |$ z2 rchanges in RGS2 expression have been described in astrocytes,
) [" P5 k$ Y" i6 sand these changes are associated with intracellular signaling
- [6 D6 @0 g7 g2 U" r3 Q) mcascades, suggesting that RGS2 upregulation may be an important
0 m: p) N7 ]5 b- ]- R2 _; `mechanism by which astrocytes may regulate RGS2 function in
7 x) F5 S4 G' J, i# k* V8 jresponse to physiological stress. However, information on the
+ m6 \) g# c0 q( R6 qfunctional roles of stress-induced modulation of RGS2 protein
5 \- e- ^! V- v: T# b! ^expression in astrocyte function is limited. We report the role of
4 b3 a& y! |# \4 O- {( `ischemic stress in RGS2 protein expression in rat C6 astrocytoma
4 |& X. n; t- { i. m/ W( Zcells and primary mouse astrocytes. A marked increase in RGS2
& H3 c& E2 j4 J) D+ F1 T% soccurred after ischemic stress induced by chemicals (sodium azide- {: G% S( D! V7 V' h: E, v
and 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real& I! U: `, x9 e* Q& F2 O
ischemia). RGS2 mRNA expression was markedly enhanced by 1
: O8 G E$ a1 P( D Ah of exposure to chemical ischemia or 6 h of OGD followed by 2
1 P R8 \. b6 {1 @or 6 h of recovery, respectively. This enhanced expression in
2 X, c( E& E* H+ G4 I/ ^- kprimary astrocytes and C6 cells was restored to baseline levels
. H% a; E; V/ Tafter 12 h of recovery from chemically induced ischemic stress or/ }% V4 u4 E* P, r+ w$ |( s
4 – 6 h of recovery from OGD. RGS2 protein was also significantly
4 E' [, \ a# `- ?# q' ]expressed at 12–24 h of recovery from ischemic insult. Ischemiainduced. Y! b' l0 X9 |, u5 }3 t
RGS2 upregulation was associated with enhanced apoptosis.
& _4 J" f6 N. Y( PIt significantly increased annexin V-positive cells, cleaved
9 q H9 ?! d1 H& L; R8 ]caspase-3, and enhanced DNA ladder formation and cell cycle
1 z! V2 Y& i0 L' s& Farrest. However, a small interfering RNA (siRNA)-mediated RGS2
# v Z$ a1 ?3 a& @. H; vknockdown reversed the apoptotic cell death associated with ischemia-; S$ D5 l- h: C" D5 Z6 m. d
induced RGS2 upregulation. Upregulated RGS2 was significantly
+ F/ {$ w1 k$ r- Sinhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin,
- i/ E) x: t4 h6 u/ n8 E5 Ta potent inhibitor of PKC, completely abrogated the increased) D1 @3 G* V& I. e U
RGS2 expression. We also examine whether ischemia-induced$ @+ B$ ]. v( p# e4 l' I
RGS2-mediated apoptosis is affected by siRNA-targeted endogenous
; q# T9 d" d: o8 j2 o @" ^! gPKC downregulation or its phosphorylation. Although
; F/ I% y! G; e5 Y: m2 RRGS2 upregulation was not affected, siRNA transfection significantly
# u6 [; U5 T' E* a) O: `suppressed endogenous PKC mRNA and protein expresexpressions.! Y0 ? w4 p2 A5 K# m8 {. Q1 R
Ischemia-induced PKC phosphorylation and caspase-3' x8 }* K1 {! f
cleavage were dose dependently inhibited by PKC knockdown,
4 D' H; H% x% m( |5 T7 pand this endogenous PKC suppression reversed ischemia-induced
4 Z7 _8 Y4 k+ Y+ D8 q9 h5 vannexin V-positive cells. This study suggests that ischemic stress
O1 ~. h' p! P* h/ B" |" C* rincreases RGS2 expression and that this condition contributes to2 g2 s2 V8 F* ?; Q7 l
enhanced apoptosis in C6 cells and primary astrocytes. The signaling0 l. \3 E9 H0 a( T2 l4 d* }5 q
it follows may involve PKC and p38 MAPK pathways./ k3 \+ ]8 U w4 k+ B
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发表于 2011-8-24 05:41
