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Ischemia induces regulator of G protein signaling 2 (RGS2) protein
; {5 f! U% k$ z6 q3 @! |8 P) N" \) f% Fupregulation and enhances apoptosis in astrocytes% \# r6 P5 O( c+ W
Mehari Endale,1* Sung Dae Kim,1* Whi Min Lee,1 Sangseop Kim,2 Kyoungho Suk,2 Jae Youl Cho,3
. j; x1 t+ }; v. SHwa Jin Park,4 Yadav Wagley,5 Suk Kim,6 Jae-Wook Oh,5 and Man Hee Rhee1( m% x, R" K& Z" u1 l
0 i6 Z& C' `0 I/ k
Endale M, Kim SD, Lee WM, Kim S, Suk K, Cho JY, Park HJ,
" n/ z4 H. n! h3 w# l; ^7 QWagley Y, Kim S, Oh JW, Rhee MH. Ischemia induces regulator of G
3 J8 E0 [" x, ]! Y! H; T- A+ ]1 iprotein signaling 2 (RGS2) protein upregulation and enhances apoptosis3 M u5 p, ~3 W: @. _
in astrocytes. Am J Physiol Cell Physiol 298: C611–C623, 2010. First
: G; K! M2 w5 A0 [published December 23, 2009; doi:10.1152/ajpcell.00517.2008.—Regulator
6 j* p7 |! ~$ D& z" K5 _- `of G protein signaling (RGS) family members, such as RGS2,5 I& _7 \. @1 R9 D3 S, G
interact with G subunits of heterotrimeric G proteins, accelerating
# \6 X+ p U( ^: L u- }the rate of GTP hydrolysis and attenuating the intracellular signaling& ]$ d- m1 r. o8 k; @
triggered by the G protein-coupled receptor-ligand interaction." C7 f1 i: R& I0 s: M
They are also reported to regulate G protein-effector interactions
7 l0 D0 m3 f2 n' w, Z! band form multiprotein signaling complexes. Ischemic stress-induced
9 t6 P$ r$ c3 P) Jchanges in RGS2 expression have been described in astrocytes,* g8 q$ Q! N. J: f
and these changes are associated with intracellular signaling
' t& @" L# Q0 I1 L: jcascades, suggesting that RGS2 upregulation may be an important5 c6 f; G: _$ B# Y U
mechanism by which astrocytes may regulate RGS2 function in
7 w8 \2 o7 G" n- Cresponse to physiological stress. However, information on the
1 I+ {& F# H8 F& y( xfunctional roles of stress-induced modulation of RGS2 protein
0 ?6 s- H: c; ^) `, j, w+ xexpression in astrocyte function is limited. We report the role of% ~* z) f0 J v& y" p0 p! q, J7 F) Q E
ischemic stress in RGS2 protein expression in rat C6 astrocytoma
2 x$ |7 `& F/ Ocells and primary mouse astrocytes. A marked increase in RGS26 d9 d+ K0 }( B$ J$ Z
occurred after ischemic stress induced by chemicals (sodium azide: O, M5 _5 S0 o' e6 B9 `( i
and 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real
, ^. b( M5 Z$ Q4 I4 \ischemia). RGS2 mRNA expression was markedly enhanced by 1
, Z2 w' _4 L) Z: Vh of exposure to chemical ischemia or 6 h of OGD followed by 2
- ^ o8 Y* m: e4 o+ H0 Hor 6 h of recovery, respectively. This enhanced expression in
8 x! z' T; \) X8 P1 G9 R. v! o, z5 n& x. uprimary astrocytes and C6 cells was restored to baseline levels. C' p5 n- P3 M
after 12 h of recovery from chemically induced ischemic stress or
* T+ b' A9 U: n) q" x4 – 6 h of recovery from OGD. RGS2 protein was also significantly1 c& p4 g4 T) L; _
expressed at 12–24 h of recovery from ischemic insult. Ischemiainduced
9 x3 ~ {$ ~$ n) j0 k! RRGS2 upregulation was associated with enhanced apoptosis.* }( Y( K; x& I; _
It significantly increased annexin V-positive cells, cleaved) A9 |9 k# i* P b1 i) a
caspase-3, and enhanced DNA ladder formation and cell cycle
( h/ ?0 p$ S, N- j2 qarrest. However, a small interfering RNA (siRNA)-mediated RGS2
& L) h2 @6 y v; [knockdown reversed the apoptotic cell death associated with ischemia-
M8 P v( ~6 l, s$ o& F7 @induced RGS2 upregulation. Upregulated RGS2 was significantly8 _. d2 d, B" |2 l: K
inhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin,( i, ~7 `9 M4 T g2 S5 A
a potent inhibitor of PKC, completely abrogated the increased( h6 ^1 K' ]0 M3 _$ F3 L
RGS2 expression. We also examine whether ischemia-induced9 i- T! T# d2 `/ _
RGS2-mediated apoptosis is affected by siRNA-targeted endogenous( B2 B+ w; u! T
PKC downregulation or its phosphorylation. Although
* B% _% y+ \ U' Z. U- [+ H8 e+ jRGS2 upregulation was not affected, siRNA transfection significantly* c( r" N- ^: T$ j! y: v- ]
suppressed endogenous PKC mRNA and protein expresexpressions.
. C1 [$ S5 T: E5 G, ^Ischemia-induced PKC phosphorylation and caspase-32 L) R/ w _8 B' e
cleavage were dose dependently inhibited by PKC knockdown,, V9 n5 x( @+ j9 A o
and this endogenous PKC suppression reversed ischemia-induced
+ F+ v% q1 q h& T% Dannexin V-positive cells. This study suggests that ischemic stress+ ]2 j# ?/ o0 j# _+ O M7 }& m! l
increases RGS2 expression and that this condition contributes to
! Q+ c$ p; _+ r4 henhanced apoptosis in C6 cells and primary astrocytes. The signaling
& T7 Z# U( v5 F8 X `9 C0 h5 vit follows may involve PKC and p38 MAPK pathways.
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发表于 2011-8-24 05:41
