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Ischemia induces regulator of G protein signaling 2 (RGS2) protein
3 I" `& O2 l% mupregulation and enhances apoptosis in astrocytes: y6 O/ p/ l9 v
Mehari Endale,1* Sung Dae Kim,1* Whi Min Lee,1 Sangseop Kim,2 Kyoungho Suk,2 Jae Youl Cho,3
1 {' N0 D: ~& V: q$ uHwa Jin Park,4 Yadav Wagley,5 Suk Kim,6 Jae-Wook Oh,5 and Man Hee Rhee1- r* D. g% K' u1 I' _
. L: @" `8 b& q& P# Y
Endale M, Kim SD, Lee WM, Kim S, Suk K, Cho JY, Park HJ,
: ^5 S, Z& Y& v1 S" fWagley Y, Kim S, Oh JW, Rhee MH. Ischemia induces regulator of G3 y5 b8 Y$ x% E& f$ r* x6 c/ ]
protein signaling 2 (RGS2) protein upregulation and enhances apoptosis$ M& o5 g: f& c* W) ^5 `
in astrocytes. Am J Physiol Cell Physiol 298: C611–C623, 2010. First
, ~- G4 q( p H/ u4 Zpublished December 23, 2009; doi:10.1152/ajpcell.00517.2008.—Regulator
9 ?* O9 S* d& L& ~3 `; Yof G protein signaling (RGS) family members, such as RGS2,
- [1 m, v) _6 |/ l8 rinteract with G subunits of heterotrimeric G proteins, accelerating" [8 O6 f5 ~- u: g$ \0 l' }% _$ w7 m
the rate of GTP hydrolysis and attenuating the intracellular signaling
5 m7 Y1 m1 p* d( k, a7 U2 Utriggered by the G protein-coupled receptor-ligand interaction.2 Q+ t. [! p( ?! }* n
They are also reported to regulate G protein-effector interactions
& b1 k( @- ~# A5 S6 F* sand form multiprotein signaling complexes. Ischemic stress-induced1 }' \/ C: S/ h2 {) Z7 O( @
changes in RGS2 expression have been described in astrocytes,
) m5 I) ]7 v( L5 B4 @" z: q: Qand these changes are associated with intracellular signaling
! ], I6 l5 R- E: X9 y! Lcascades, suggesting that RGS2 upregulation may be an important
; B4 N% d2 U2 U+ rmechanism by which astrocytes may regulate RGS2 function in
2 N( Y( d1 o& C% mresponse to physiological stress. However, information on the
$ X& o8 @7 T4 `; p( ^& jfunctional roles of stress-induced modulation of RGS2 protein
$ u1 {0 u; M7 l [6 Oexpression in astrocyte function is limited. We report the role of4 Y2 M K- r. P1 Y* i
ischemic stress in RGS2 protein expression in rat C6 astrocytoma
. m( y2 ?* M# u& Qcells and primary mouse astrocytes. A marked increase in RGS2
t) o9 A# ^& r5 W! ]4 y y3 qoccurred after ischemic stress induced by chemicals (sodium azide: S, n: I5 I, s0 Z$ i7 k1 g
and 2-deoxyglucose) or oxygen-glucose deprivation (OGD, real" B! V) A u, j Y; [
ischemia). RGS2 mRNA expression was markedly enhanced by 1
0 A e! ^& e: l7 e; v6 e" _h of exposure to chemical ischemia or 6 h of OGD followed by 24 w& H: y' o. Q
or 6 h of recovery, respectively. This enhanced expression in/ k& T# T8 ?2 c" b9 O
primary astrocytes and C6 cells was restored to baseline levels
, v1 D# B7 B( A; [, w& E3 Vafter 12 h of recovery from chemically induced ischemic stress or
( m( W& d# [7 E+ Z4 – 6 h of recovery from OGD. RGS2 protein was also significantly
2 K2 n: o5 h+ E5 b/ q0 X5 xexpressed at 12–24 h of recovery from ischemic insult. Ischemiainduced) f$ }5 V3 H, v& w
RGS2 upregulation was associated with enhanced apoptosis.
g& J4 B2 _, ] x$ @& g* Z7 gIt significantly increased annexin V-positive cells, cleaved
, l- T1 e: ~0 lcaspase-3, and enhanced DNA ladder formation and cell cycle
% |, @% w/ v( O5 g6 x' jarrest. However, a small interfering RNA (siRNA)-mediated RGS2% c$ K7 D9 @, g5 r$ D3 m
knockdown reversed the apoptotic cell death associated with ischemia-
* M! _- V9 v: Y7 r. E3 Ginduced RGS2 upregulation. Upregulated RGS2 was significantly
% R8 l- ]4 Y% J0 S$ v% k/ @inhibited by SB-203580, a p38 MAPK inhibitor. Rottlerin,
f4 s9 _$ @; f+ Ga potent inhibitor of PKC, completely abrogated the increased
2 U8 d8 F# w2 \3 T" ?; d rRGS2 expression. We also examine whether ischemia-induced' c; l2 a) U b
RGS2-mediated apoptosis is affected by siRNA-targeted endogenous" R, I% W1 p; O( S% d7 u
PKC downregulation or its phosphorylation. Although
( V. `9 y) f* C% i% U' D# V7 }2 bRGS2 upregulation was not affected, siRNA transfection significantly4 @1 t8 C# R' c P. e, G1 R
suppressed endogenous PKC mRNA and protein expresexpressions.
4 G, A) W! o7 ]0 `9 SIschemia-induced PKC phosphorylation and caspase-3
' y) n- K3 w) e& t3 bcleavage were dose dependently inhibited by PKC knockdown,* O- a5 v+ O) q" t Y8 I5 @
and this endogenous PKC suppression reversed ischemia-induced
* {1 l1 n* `3 |- Z$ h3 tannexin V-positive cells. This study suggests that ischemic stress
8 p/ J: t4 k- ?. wincreases RGS2 expression and that this condition contributes to! f' t! G) \* }" y' {& O
enhanced apoptosis in C6 cells and primary astrocytes. The signaling
, x8 V% Z1 x: c- I$ a2 j. ^it follows may involve PKC and p38 MAPK pathways.
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发表于 2011-8-24 05:41
