Activation of the Transient Receptor Potential Vanilloid-1 (TRPV1) channel mediates Extracellular Signal Regulated Kinase (ERK) phosphorylation via Beta-arrestin-2 signaling

Date
2015-03-25
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Abstract
The Transient Receptor Potential Vanilloid 1 (TRPV1) channel plays a pivotal role in pain sensation and transduction under physiological and pathophysiological conditions. Recent work highlighted a possible role for β-arrestin-2, a scaffolding protein that mediates G-protein coupled receptor desensitization, in channel regulation. Interestingly, β-arrestin-2 also acts as a signaling scaffold for the MAPK (ERK1/2) pathway which was described as an important nociceptive marker. In this thesis, several experimental approaches were employed to investigate TRPV1 signaling and to characterize whether β-arrestin-2 as well as ERK play a role downstream of channel activation. The work presented here describes for the first time a unique β-arrestin-2 signaling pathway following TRPV1 channel activation. In particular, we found that calcium influx through TRPV1 channels induced translocation of β-arrestin-2 from the cytosol to the nucleus. In addition, we showed that TRPV1 activation elicited ERK phosphorylation in a β-arrestin-2-dependent manner. Our data suggest that the signaling cascade starts with calcium influx through TRPV1 channels that activates protein kinase C (PKC) and induces its translocation to the plasma membrane. The activation of PKC was necessary for ERK activation as well as β-arrestin-2 nuclear translocation. While this work is the first to describe β-arrestin-2 nuclear translocation downstream of TRPV1 stimulation, the functional relevance of this translocation is yet-to-be unveiled. Given the crucial role of TRPV1 in nociception, understanding its signaling as well as the mechanisms by which the channel is modulated may pave the way to develop a novel class of analgesics.
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Keywords
Pharmacology
Citation
Aboushousha, R. (2015). Activation of the Transient Receptor Potential Vanilloid-1 (TRPV1) channel mediates Extracellular Signal Regulated Kinase (ERK) phosphorylation via Beta-arrestin-2 signaling (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/24691