TY - JOUR
T1 - The V2 vasopressin receptor stimulates ERK1/2 activity independently of heterotrimeric G protein signalling
AU - Charest, Pascale G.
AU - Oligny-Longpré, Geneviève
AU - Bonin, Hélène
AU - Azzi, Mounia
AU - Bouvier, Michel
N1 - Funding Information:
This work was supported by grants from the Canadian Institute for Health Research and the Quebec Heart and Stroke Foundation. P.G.C. was supported by doctoral studentships from the Heart and Stroke Foundation of Canada and the Fonds de Recherche en Santé du Québec; G.O.-L. was supported by a studentship from the Natural Sciences and Engineering Research Council of Canada; M.A. was supported by a post-doctoral fellowship from the Canadian Hypertension Society; and M.B. holds a Canada Research Chair in Signal Transduction and Molecular Pharmacology. We are grateful to Dr. Monique Lagacé for critical reading of the manuscript.
PY - 2007/1
Y1 - 2007/1
N2 - The V2 vasopressin receptor (V2R) activates the mitogen activated protein kinases (MAPK) ERK1/2 through a mechanism involving the scaffolding protein βarrestin. Here we report that this activating pathway is independent of Gαs, Gαi, Gαq or Gβγ and that the V2R-mediated activation of Gαs inhibits ERK1/2 activity in a cAMP/PKA-dependent manner. In the HEK293 cells studied, the βarrestin-promoted activation was found to dominate over the PKA-mediated inhibition of the pathway, leading to a strong vasopressin-stimulated ERK1/2 activation. Despite the strong MAPK activation and in contrast with other GPCR, V2R did not induce any significant increase in DNA synthesis, consistent with the notion that the stable interaction between V2R and βarrestin prevents signal propagation to the nucleus. βarrestin was found to be essential for the ERK1/2 activation, indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues. Based on the use of selective pharmacological inhibitors, dominant negative mutants and siRNA, we conclude that the βarrestin-dependent activation of ERK1/2 by the V2R involves c-Src and a metalloproteinase-dependent trans-activation event. These findings demonstrate that βarrestin is a genuine signalling initiator that can, on its own, engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand.
AB - The V2 vasopressin receptor (V2R) activates the mitogen activated protein kinases (MAPK) ERK1/2 through a mechanism involving the scaffolding protein βarrestin. Here we report that this activating pathway is independent of Gαs, Gαi, Gαq or Gβγ and that the V2R-mediated activation of Gαs inhibits ERK1/2 activity in a cAMP/PKA-dependent manner. In the HEK293 cells studied, the βarrestin-promoted activation was found to dominate over the PKA-mediated inhibition of the pathway, leading to a strong vasopressin-stimulated ERK1/2 activation. Despite the strong MAPK activation and in contrast with other GPCR, V2R did not induce any significant increase in DNA synthesis, consistent with the notion that the stable interaction between V2R and βarrestin prevents signal propagation to the nucleus. βarrestin was found to be essential for the ERK1/2 activation, indicating that the recruitment of the scaffolding protein is necessary and sufficient to initiate the signal in the absence of any other stimulatory cues. Based on the use of selective pharmacological inhibitors, dominant negative mutants and siRNA, we conclude that the βarrestin-dependent activation of ERK1/2 by the V2R involves c-Src and a metalloproteinase-dependent trans-activation event. These findings demonstrate that βarrestin is a genuine signalling initiator that can, on its own, engage a MAPK activation machinery upon stimulation of a GPCR by its natural ligand.
KW - Extra-cellular signal-regulated kinases 1 and 2
KW - GPCR
KW - MAPK
KW - V2 vasopressin receptor
KW - βarrestin
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U2 - 10.1016/j.cellsig.2006.05.020
DO - 10.1016/j.cellsig.2006.05.020
M3 - Article
C2 - 16857342
AN - SCOPUS:33845316454
VL - 19
SP - 32
EP - 41
JO - Cellular Signalling
JF - Cellular Signalling
SN - 0898-6568
IS - 1
ER -