Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium

作者：Lau Chang; Lytle Christian; Straus Daniel S; DeFea Kathryn A^*

来源：American Journal of Physiology - Cell Physiology, 2011, 300(1): C113-C123.

DOI：10.1152/ajpcell.00162.2010

• arrestin
• extracellular signal-regulated kinase 1/2
• signal transduction
• cofilin

Lau C, Lytle C, Straus DS, DeFea KA. Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium. Am J Physiol Cell Physiol 300: C113-C123, 2011. First published November 10, 2010; doi: 10.1152/ajpcell.00162.2010.-Studies suggest that there are two distinct pools of proteinase-activated receptor-2 (PAR(2)) present in intestinal epithelial cells: an apical pool accessible from the lumen, and a basolateral pool accessible from the interstitial space and blood. Although introduction of PAR(2) agonists such as 2-furoyl-LIGRL-O-NH(2) (2fAP) to the intestinal lumen can activate PAR(2), the presence of accessible apical PAR(2) has not been definitively shown. Furthermore, some studies have suggested that basolateral PAR(2) responses in the intestinal epithelium are mediated indirectly by neuropeptides released from enteric nerve fibers, rather than by intestinal PAR(2) itself. Here we identified accessible pools of both apical and basolateral PAR(2) in cultured Caco(2)-BBe monolayers and in mouse ileum. Activation of basolateral PAR(2) transiently increased short-circuit current by activating electrogenic Cl(-) secretion, promoted dephosphorylation of the actin filament-severing protein, cofilin, and activated the transcription factor, AP-1, whereas apical PAR(2) did not. In contrast, both pools of PAR(2) activated extracellular signal-regulated kinase 1/2 (ERK1/2) via temporally and mechanistically distinct pathways. Apical PAR(2) promoted a rapid, biphasic PLC+/Ca(2+)/PKC-dependent ERK1/2 activation, resulting in nuclear localization, whereas basolateral PAR(2) promoted delayed ERK1/2 activation which was predominantly restricted to the cytosol, involving both PLC+/Ca(2+) and beta-arrestin-dependent pathways. These results suggest that the outcome of PAR(2) activation is dependent on the specific receptor pool that is activated, allowing for fine-tuning of the physiological responses to different agonists.

• 出版日期2011-1