Mechanisms of Intestinal Serotonin Transporter (SERT) Upregulation by TGF-β1 Induced Non-Smad Pathways

被引：20

作者：

Nazir, Saad ^{[1
]}

Kumar, Anoop ^{[1
]}

Chatterjee, Ishita ^{[1
]}

Anbazhagan, Arivarasu N. ^{[1
]}

Gujral, Tarunmeet ^{[1
]}

Priyamvada, Shubha ^{[1
]}

Saksena, Seema ^{[1
]}

Alrefai, Waddah A. ^{[1
,2
]}

Dudeja, Pradeep K. ^{[1
,2
]}

Gill, Ravinder K. ^{[1
]}

机构：

[1] Univ Illinois, Div Gastroenterol & Hepatol, Dept Med, Chicago, IL 60607 USA

[2] Jesse Brown VA Med Ctr, Chicago, IL USA

来源：

PLOS ONE | 2015年 / 10卷 / 05期

关键词：

GROWTH-FACTOR-BETA; INFLAMMATORY-BOWEL-DISEASE; NA+/H+ EXCHANGER-3 NHE3; EPITHELIAL-CELLS; SYNTAXIN; 1A; TGF-BETA; ULCERATIVE-COLITIS; EXOCYTOSIS; EXPRESSION; 5-HYDROXYTRYPTAMINE;

D O I：

10.1371/journal.pone.0120447

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

TGF-beta 1 is an important multifunctional cytokine with numerous protective effects on intestinal mucosa. The influence of TGF-beta 1 on serotonin transporter (SERT) activity, the critical mechanism regulating the extracellular availability of serotonin (5-HT), is not known. Current studies were designed to examine acute effects of TGF-beta 1 on SERT. Model human intestinal Caco-2 cells grown as monolayer's or as cysts in 3D culture and ex vivo mouse model were utilized. Treatment of Caco-2 cells with TGF-beta 1 (10 ng/ml, 60 min) stimulated SERT activity (similar to 2 fold, P<0.005). This stimulation of SERT function was dependent upon activation of TGF-beta 1 receptor (TGFRI) as SB-431542, a specific TGF-beta RI inhibitor blocked the SERT stimulation. SERT activation in response to TGF-beta 1 was attenuated by inhibition of PI3K and occurred via enhanced recruitment of SERT-GFP to apical surface in a PI3K dependent manner. The exocytosis inhibitor brefeldin A (2.5 mu M) attenuated the TGF-beta 1-mediated increase in SERT function. TGF-beta 1 increased the association of SERT with the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) syntaxin 3 (STX3) and promoted exocytosis of SERT. Caco-2 cells grown as cysts in 3D culture recapitulated the effects of TGF-beta 1 showing increased luminal staining of SERT. Ussing chamber studies revealed increase in H-3-5-HT uptake in mouse ileum treated ex vivo with TGF-beta 1 (10 ng/ml, 1h). These data demonstrate a novel mechanism rapidly regulating intestinal SERT via PI3K and STX3. Since decreased SERT is implicated in various gastro-intestinal disorders e.g IBD, IBS and diarrhea, understanding mechanisms stimulating SERT function by TGF-beta 1 offers a novel therapeutic strategy to treat GI disorders.

引用

页数：17

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