The transient receptor potential channels, ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), are non-selective cation-permeable channels that have retained their function as chemical sensors since their first appearance in metazoan species several hundred million years ago. In vertebrates, TRP channels have evolved multiple functions which make it difficult to understand exactly how they transmit signals to the brain that are interpreted very differently. For example, TRPA1 and TRPV1 are sensitive to various chemicals and activation of these channels produce sensations with opposing effects. Pain is felt when TRPV1 is activated by spider toxins, but activation by plant cannabidiol results in a pain-relieving sensation. Similarly, TRPA1 activation by delta-tetrahydrocannabinol is reported to relieve symptoms of pain, but TRPA1 activation by the active ingredient in wasabi results in a repulsive or noxious sensation. Much of what we know about TRPA1 and TRPV1 comes from the use of plant products or exposure to substances that cause or alleviate pain and inflammation. In this study, whole-cell voltage clamp recordings of heterologously expressed human TRPA1 and human TRPV1 were tested for sensitivity to a hallucinogenic plant compound, salvinorin A and an arthropod-defensive compound, para-benzoquinone. Neither compound has yet been reported to activate TRP channels but both are known to be involved in pain and inflammation signaling in humans. I show that the arthropod compound, para-benzoquinone, activates and desensitizes TRPA1 in a cysteine-dependent manner, but activation of TRPV1 is not dependent on cysteine reactivity. Although salvinorin A is known to be a potent agonist of the kappa-opioid and cannabinoid receptors, here I show that it also acts as a highly potent agonist of both TRPA1 and TRPV1. Its interaction with TRP channels may contribute to its antinociceptive effects in behavioral studies with animals that are reported to be independent of opioid signaling.
|Advisor:||Clapham, David E.|
|Commitee:||Bean, Bruce, Paul, David, Yellen, Gary|
|Department:||Biology: Medical Sciences, Division of|
|School Location:||United States -- Massachusetts|
|Source:||DAI-B 74/10(E), Dissertation Abstracts International|
|Keywords:||Ankyrin, Ion channels, Opioid signaling, Pain signaling, Vanilloid|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be