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Am J Physiol Gastrointest Liver Physiol 295: G700-G708, 2008. First published July 31, 2008; doi:10.1152/ajpgi.90362.2008
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MUCOSAL BIOLOGY

Serotonin modifies cytoskeleton and brush-border membrane architecture in human intestinal epithelial cells

Ravinder K. Gill,1,* Le Shen,3 Jerrold R. Turner,3 Seema Saksena,1 Waddah A. Alrefai,1 Nitika Pant,2 Ali Esmaili,1 Alka Dwivedi,1 Krishnamurthy Ramaswamy,1,2 and Pradeep K. Dudeja1,2,*

1Section of Digestive Diseases and Nutrition, Department of Medicine, University of Illinois at Chicago; 2Jesse Brown Veterans Affairs Medical Center and 3Department of Pathology, the University of Chicago, Chicago, Illinois

Submitted 31 May 2008 ; accepted in final form 28 July 2008

Serotonin or 5-hydroxytryptamine (5-HT) influences numerous functions in the gastrointestinal tract. We previously demonstrated that 5-HT treatment of Caco-2 cells inhibited Na+/H+ exchangers (NHE) and Cl–/OH– exchange activities via distinct signaling mechanisms. Since regulation of several ion transporters such as NHE3 is influenced by intact cytoskeleton, we hypothesized that 5-HT modifies actin cytoskeleton and/or brush-border membrane architecture via involvement of signaling pathways. Ultrastructural analysis showed that 5-HT (0.1 µM, 1 h) treatment of Caco-2 cells caused the apical membrane to assume a convex dome shape that was associated with shortening of microvilli. To examine whether these cellular architecture changes are cytoskeleton driven, we analyzed actin cytoskeleton by fluorescence microscopy. 5-HT induced basal stress fibers with prominent cortical actin filaments via 5-HT3 and 5-HT4 receptor subtypes. This induction was partially attenuated by chelation of intracellular Ca2+ and PKC{alpha} inhibition (Go6976). In vitro assays revealed that PKC{alpha} interacted with actin and this association was increased by 5-HT. Our data provide novel evidence that 5-HT-induced signaling via 5-HT3/4 receptor subtypes to cause Ca2+ and PKC{alpha}-dependent regulation of actin cytoskeleton may play an important role in modulation of ion transporters that contribute to pathophysiology of diarrheal conditions associated with elevated levels of 5-HT.

microvilli; serotonin and actin; 5-HT and curvature; stress fibers; ion transporter; cytoskeleton


Address for reprint requests and other correspondence: R. K. Gill, Dept. of Medicine, Univ. of Illinois at Chicago, Medical Research Service (600/151), Jesse Brown VA Medical Center, 820 S. Damen Ave., Chicago, IL 60612 (e-mail: rgill{at}uic.edu)






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