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

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.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Medical Science

Grantor dc:publisher.institution

Graduate Studies

Year dc:date.issued

2015

Author dc:creator

• Aboushousha, Reem

Advisor dc:contributor.advisor

• Altier, Christophe

• Pharmacology

Statement dc:rights

• University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.

Language dc:language.iso

eng

DOI

http://dx.doi.org/10.11575/PRISM/24691

OAI identifier oai:identifier

oai:ucalgary.scholaris.ca:11023/2123