Multimodal regulation of transient receptor potential ion channels

2008 2008

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Abstract (summary)

Nociceptive Transient Receptor Potential (TRP) ion channels are of paramount importance to the general public as they are potential targets for the development of novel analgesics. Here, we identify novel agonists for some of these ion channels and explore their clinical relevance in pain behavioral models. We found omega-3 fatty acids can directly activate TRPV1. In contrast to their agonistic properties, omega-3 fatty acids competitively inhibit the responses of vanilloid agonists. Significantly, docosahexaenoic acid exhibits the greatest efficacy as an agonist, whereas eicosapentaenoic acid and linolenic acid are markedly more effective inhibitors. Similarly, eicosapentaenoic but not docosahexaenoic acid profoundly reduces capsaicin-evoked pain-related behavior in mice.

General anesthetics (GAs) have transformed surgery through their actions to depress the central nervous system and blunt the perception of surgical insults. However, many of these agents activate peripheral nociceptive neurons and the underlying mechanisms and significance of these effects have not been explored. Here, we show that clinical concentrations of noxious intravenous and inhalation GAs excite sensory neurons by selectively activating TRPA1, a key ion channel in the pain pathway. Further, these GAs induce pain-related behavior in mice that is abolished in TRPA1-null animals. Significantly, neurogenic inflammation is greater in mice anesthetized with pungent compared with non-pungent anesthetics. Thus, these data reveal the mechanism by which GAs activate and sensitize peripheral nociceptors.

TRPV1 and TRPM8 are sensory nerve ion channels activated by heating and cooling respectively. A variety of physical and chemical stimuli activate these receptors in a synergistic manner but the underlying mechanisms are unclear. Both channels are voltage-sensitive, and temperature and ligands modulate this voltage dependence. We show here that voltage produces only a partial activation of TRPV1 and TRPM8. Furthermore, high concentrations of capsaicin, resiniferatoxin, and menthol reveal voltage-independent gating. Similarly, other modes of TRPV1 regulation including heat, protein kinase C-dependent phosphorylation, and protons enhance both the efficacy and sensitivity of voltage activation. In contrast, the TRPV1 antagonist, capsazepine, produces the opposite effects. These data can be explained by an allosteric model in which voltage, temperature, agonists and inverse agonists are independently coupled, either positively or negatively, to channel gating.

Indexing (details)

0317: Neurosciences
0719: Physiology
Identifier / keyword
Biological sciences; General anesthetics; Ion channels; Omega-3 fatty acids; Transient receptor potential
Multimodal regulation of transient receptor potential ion channels
Matta, Jose Antonio
Number of pages
Publication year
Degree date
School code
DAI-B 69/08, Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Ahern, Gerard P.
Georgetown University Medical Center
University location
United States -- District of Columbia
Source type
Dissertations & Theses
Document type
Dissertation/thesis number
ProQuest document ID
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
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