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FUNCTIONAL REGULATION OF THE NEURONAL COLD SENSOR TRPM8
by
Richard Luke Daniels
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(NEUROSCIENCE)
December 2009
Copyright 2009 Richard Luke Daniels
Object Description
| Title | Functional regulation of the neuronal cold sensor TRPM8 |
| Author | Daniels, Richard Luke |
| Author email | rldaniel@usc.edu; ldaniels@spu.edu |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Neuroscience |
| School | College of Letters, Arts and Sciences |
| Date defended/completed | 2009-07-22 |
| Date submitted | 2009 |
| Restricted until | Unrestricted |
| Date published | 2009-08-21 |
| Advisor (committee chair) | McKemy, David D. |
| Advisor (committee member) |
Liman, Emily R. Chan, Jonah R. Yu, Alan S. L. |
| Abstract | The ability to detect cold temperatures is critical for survival. Cold-sensing neurons play important roles in thermosensation, pain sensation (nociception), thermoregulation, cooling-induced analgesia, and smooth muscle reflexes in the bladder and airway. At the molecular level, cold is detected by TRPM8, a non-selective cation channel expressed in a subset of primary afferent neurons. Genetic disruption of TRPM8 leads to severe deficits in cold-sensing, confirming the role of TRPM8 as the primary transducer of cold temperatures.; Though TRPM8 is primarily a neuronal cold sensor, its activity is modulated by a number of factors, including temperature, membrane voltage, membrane lipids, intracellular pH, natural and synthetic cooling compounds such as menthol and icilin, and several chemical antagonists. Therefore in order to understand the neuronal substrates of cold-sensing, it is necessary to understand how these various elements regulate TRPM8 function.; Here we describe a molecular pathway that governs TRPM8 adaptation, a phenomenon where TRPM8 activity decreases even as a cold stimulus persists. Adaptation is thought to lead directly to neuronal adaptation and provide an organism with the means to discriminate subtle temperature changes. We determine that TRPM8 activity initiates a negative feedback loop where calcium entry through the channel leads to Phospholipase C (PLC) activation and subsequent hydrolyzation of its substrate, the membrane phospholipid phosphoinositol-4,5-bisphosphate (PIP2). We find that diminished PIP2 levels decrease TRPM8 activity in neurons. Moreover, we find that PLC activation and PIP2 reduction do not alter the temperature sensitivity of the channel, but do shift the voltage-dependence of channel gating.; In addition to characterizing this adaptive regulatory mechanism, we demonstrate that two novel compounds act as selective antagonists, functionally inhibiting TRPM8 but not the activity of related TRP channels. We determine that TRPM8 antagonism shifts the voltage-dependence of channel gating.; Lastly, we describe the creation of a computer controlled thermal preference assay chamber, useful for investigating the physiological effects of functional TRPM8 regulation.; The adaptive model we have presented, together with the characterization of novel TRPM8 antagonists, provides insight into the molecular regulation of TRPM8 function and suggests potential drug targets and pharmacological tools that manipulate the excitability of cold-sensing neurons. |
| Keyword | molecular biology; neuroscience; sensory biology; somatosensation; temperature; TRPM8; ion channels; physiology; PLC; PIP2; cold; cool |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m2575 |
| Rights | Daniels, Richard Luke |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Daniels-2986 |
| Archival file | uscthesesreloadpub_Volume29/etd-Daniels-2986.pdf |
Description
| Title | Page 1 |
| Full text | FUNCTIONAL REGULATION OF THE NEURONAL COLD SENSOR TRPM8 by Richard Luke Daniels A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (NEUROSCIENCE) December 2009 Copyright 2009 Richard Luke Daniels |
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