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Dissertation/Thesis Abstract

Modulation of Transient Receptor Potential Cation Channel, Subfamily A, Member 1 (TRPA1) Activity by Cdk5
by Sulak, Michael A., Ph.D., Kent State University, 2011, 92; 10631319
Abstract (Summary)

Our understanding of the molecular mechanisms for pain and temperature sensation has undergone a revolution in the last fifteen years through the characterization of receptors of the Transient Receptor Potential (TRP) superfamily. TRP receptors, non-selective cation channels with polymodal sensitivities, have emerged as key “molecular machines” for sensation of diverse stimuli, including: cold and heat, menthol, mechanical force, and tissue acidification in an inflammatory milieu.

Activation of TRPA1, a cation channel expressed in small-diameter, nociceptive neurons of the dorsal root ganglia (DRG), has been linked to both acute and chronic pain. Acting as a detector of chemical damage, TRPA1 can be activated by a large number of “irritating” compounds—the list of TRPA1 agonists has been rapidly growing, and includes nicotine, ozone, and the intravenous anesthetic, propofol. Along with its role in acute nociception, TRPA1 also responds to inflammatory signals. Tissue damage and inflammation lead to peripheral sensitization—a state linked to the onset of chronic pain disorders. While ligand activation of TRPA1 has received considerable attention, the molecular regulation of TRPA1 activity has been less carefully scrutinized. Phosphorylation of TRPA1 residues as a mechanism of regulation has yet to be documented, in marked contrast to TRPV1, the best studied TRP channel, which is known to undergo phosphorylation by multiple kinases.

Cdk5, an unusual member of the cyclin-dependent kinase family which is principally active in post-mitotic neurons, has recently emerged as a key modulator of pain signaling pathways, influencing both TRPV1 signaling and opioid tolerance. This investigation tested the hypothesis that Cdk5 modulates the activity TRPA1.

The results of this investigation provide physiological evidence for Cdk5 regulation of TRPA1 activity in DRG neurons, and are consistent with a regulatory mechanism involving direct phosphorylation of the receptor by Cdk5. Notably, no previous studies have implicated Cdk5 as a modulator of TRPA1 activity, nor have previous studies provided evidence for phosphorylation of TRPA1 residues by any kinase. These findings bolster the emerging view of Cdk5 as a potential “master regulator” of pain sensation pathways, and a promising target for novel analgesic drugs.

Indexing (document details)
Advisor: Damron, Derek
Commitee: Bratz, Ian N., Datta, Bansidhar, Dorman, Robert V., Freeman, Ernest J.
School: Kent State University
Department: College of Arts and Sciences / School of Biomedical Sciences
School Location: United States -- Ohio
Source: DAI-B 78/11(E), Dissertation Abstracts International
Subjects: Biology, Neurosciences, Cellular biology, Biomedical engineering
Keywords: Cyclin-dependent kinase 5
Publication Number: 10631319
ISBN: 978-0-355-01579-9
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