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Am J Physiol Cell Physiol. 2010 Mar;298(3):C592-601. doi: 10.1152/ajpcell.00448.2009. Epub 2009 Nov 25.

CCK activates RhoA and Rac1 differentially through Galpha13 and Galphaq in mouse pancreatic acini.

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  • 1Department of Molecular and Integrative Physiology, The University of Michigan, Ann Arbor, Michigan, USA. mesabba@umich.edu

Abstract

Cholecystokinin (CCK) has been shown to activate RhoA and Rac1, as well as reorganize the actin cytoskeleton and, thereby, modify acinar morphology and amylase secretion in mouse pancreatic acini. The aim of the present study was to determine which heterotrimeric G proteins activate RhoA and Rac1 upon CCK stimulation. Galpha(13), but not Galpha(12), was identified in mouse pancreatic acini by RT-PCR and Western blotting. Using specific assays for RhoA and Rac1 activation, we showed that only active Galpha(13) activated RhoA. By contrast, active Galpha(13) and Galpha(q), but not Galpha(s), slightly increased GTP-bound Rac1 levels. A greater increase in Rac1 activation was observed when active Galpha(13) and active Galpha(q) were coexpressed. Galpha(i) was not required for CCK-induced RhoA or Rac1 activation. The regulator of G protein signaling (RGS) domain of p115-Rho guanine nucleotide exchange factor (p115-RGS), a specific inhibitor of Galpha(12/13)-mediated signaling, abolished CCK-stimulated RhoA activation. By contrast, both RGS-2, an inhibitor of Galpha(q), and p115-RGS abolished CCK-induced Rac1 activation, which was PLC pathway-independent. Active Galpha(q) and Galpha(13), but not Galpha(s), induced morphological changes and actin redistribution similar to 1 nM CCK. CCK-induced actin cytoskeletal reorganization was inhibited by RGS-2, but not by p115-RGS, whereas CCK-induced amylase secretion was blocked by both inhibitors. Together, these findings indicate that, in mouse pancreatic acini, Galpha(13) links CCK stimulation to the activation of RhoA, whereas both Galpha(13) and Galpha(q) link CCK stimulation to the activation of Rac1. CCK-induced actin cytoskeletal reorganization is mainly mediated by Galpha(q). By contrast, Galpha(13) and Galpha(q) signaling are required for CCK-induced amylase secretion.

PMID:
19940064
[PubMed - indexed for MEDLINE]
PMCID:
PMC2838570
Free PMC Article

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