Carboxyl-terminal Domain of Transient Receptor Potential Vanilloid 1 Contains Distinct Segments Differentially Involved in Capsaicin- and Heat-induced Desensitization

Ohkita

Journal of Biological Chemistry

et al. 2016

Temperature is one of the most critical environmental factors affecting survival, and thus species that inhabit different thermal niches have evolved thermal sensitivities suitable for their respective habitats. During the process of shifting thermal niches, various types of genes expressed in diverse tissues, including those of the peripheral to central nervous systems, are potentially involved in the evolutionary changes in thermosensation. To elucidate the molecular mechanisms behind the evolution of thermosensation, thermal responses were compared between two species of clawed frogs (Xenopus laevis and Xenopus tropicalis) adapted to different thermal environments. X. laevis was much more sensitive to heat stimulation than X. tropicalis at the behavioral and neural levels. The activity and sensitivity of the heat-sensing TRPA1 channel were higher in X. laevis compared with those of X. tropicalis. The thermal responses of another heat-sensing channel, TRPV1, also differed between the two Xenopus species. The species differences in Xenopus TRPV1 heat responses were largely determined by three amino acid substitutions located in the first three ankyrin repeat domains, known to be involved in the regulation of rat TRPV1 activity. In addition, Xenopus TRPV1 exhibited drastic species differences in sensitivity to capsaicin, contained in chili peppers, between the two Xenopus species. Another single amino acid substitution within Xenopus TRPV1 is responsible for this species difference, which likely alters the neural and behavioral responses to capsaicin. These combined subtle amino acid substitutions in peripheral thermal sensors potentially serve as a driving force for the evolution of thermal and chemical sensation.Animals have evolved sophisticated physiological systems for sensing ambient temperatures, as fluctuations in environmental temperature significantly affect various biological processes. Species adapted to different thermal niches are likely to have acquired specific thermal sensitivities suitable for their respective habitats. Recent progress and understanding of the molecular mechanisms behind thermosensation has enabled us to elucidate the molecular basis for the evolution of thermosensation in the process of shifting thermal niches (1-3).In vertebrates, peripheral sensory neurons such as dorsal root ganglion (DRG) 3 and trigeminal ganglion neurons relay temperature information to the central nervous system. During the initiation of signal transduction, thermal stimuli are transduced into electrical signals and a subset of ion channels that are thermally activated plays crucial roles in this process. These ion channels belong to the transient receptor potential (TRP) ion channel superfamily and are called "thermoTRP" (1-3). Animals possess several kinds of thermoTRP channels, which have distinctive temperature ranges for activation. For example, TRPV1 is activated by heat (4 -7), whereas TRPM8 is activated by cold (1-3, 8).Temperature sensitivity among orthologous thermoTRP channels has changed duri...

Section: Discussionmentioning

confidence: 67%

Evolution of Heat Sensors Drove Shifts in Thermosensation between Xenopus Species Adapted to Different Thermal Niches

Ohkita

Journal of Biological Chemistry

et al. 2016

“…To examine changes in proteins localized to the plasma membrane, we performed biotinylation as described previously 16, 19 . Briefly, dissociated TG cells were washed three times in cold PBS.…”

Section: Methodsmentioning

confidence: 99%

Peripheral Group I Metabotropic Glutamate Receptor Activation Leads to Muscle Mechanical Hyperalgesia Through TRPV1 Phosphorylation in the Rat

Chung

Lee

Joseph

et al. 2015

The Journal of Pain

Self Cite

Elevated glutamate levels within injured muscle play important roles in muscle pain and hyperalgesia. In this study, we hypothesized that PKC-dependent TRPV1 phosphorylation contributes to the muscle mechanical hyperalgesia following activation of Group I metabotropic glutamate receptors (mGlu1/5). Mechanical hyperalgesia induced by dihydroxyphenylglycine (DHPG), an mGlu1/5 agonist, in the masseter muscle was attenuated by AMG9810, a specific TRPV1 antagonist. AMG9810 also suppressed mechanical hyperalgesia evoked by pharmacological activation of PKC. DHPG-induced mechanical hyperalgesia was suppressed by pretreatment with a decoy peptide that disrupted interactions between TRPV1 and A-kinase anchoring protein (AKAP), which facilitates phosphorylation of TRPV1. In dissociated trigeminal ganglia (TG), DHPG upregulated serine phosphorylation of TRPV1 (S800) during which DHPG-induced mechanical hyperalgesia was prominent. The TRPV1 phosphorylation at S800 was suppressed by a PKC inhibitor. Electrophysiological measurements in TG neurons demonstrated that TRPV1 sensitivity was enhanced by pretreatment with DHPG, and this was prevented by a PKC, but not by a PKA, inhibitor. These results suggest that mGlu1/5 activation in masseter afferents invoke phosphorylation of TRPV1 serine residues including S800, and that phosphorylation-induced sensitization of TRPV1 is involved in masseter mechanical hyperalgesia. These data support a role of TRPV1 as an integrator of glutamate receptor signaling in muscle nociceptors. PERSPECTIVE This article demonstrates that activation of mGlu1/5 leads to phosphorylation of a specific TRPV1 residue via PKC and AKAP150 in trigeminal sensory neurons, and that functional interactions between glutamate receptors and TRPV1 mediate mechanical hyperalgesia in the muscle tissue.

“…TRPV1 is desensitized not only by capsaicin but also heat. The mechanisms are apparently distinct [92]. Capsaicin-induced desensitization of the TRPV1 receptor requires influx of Ca 2+ through TRPV1, and depends on subsequent Ca 2+ -dependent signaling such as activation of calmodulin and calcineurin, or degradation of PIP 2 [93].…”

Section: Functional and Histological Effectsmentioning

confidence: 99%

Use of Capsaicin to Treat Pain: Mechanistic and Therapeutic Considerations

Chung

Campbell

2016

Pharmaceuticals

Self Cite

Capsaicin is the pungent ingredient of chili peppers and is approved as a topical treatment of neuropathic pain. The analgesia lasts for several months after a single treatment. Capsaicin selectively activates TRPV1, a Ca2+-permeable cationic ion channel that is enriched in the terminals of certain nociceptors. Activation is followed by a prolonged decreased response to noxious stimuli. Interest also exists in the use of injectable capsaicin as a treatment for focal pain conditions, such as arthritis and other musculoskeletal conditions. Recently injection of capsaicin showed therapeutic efficacy in patients with Morton’s neuroma, a painful foot condition associated with compression of one of the digital nerves. The relief of pain was associated with no change in tactile sensibility. Though injection evokes short term pain, the brief systemic exposure and potential to establish long term analgesia without other sensory changes creates an attractive clinical profile. Short-term and long-term effects arise from both functional and structural changes in nociceptive terminals. In this review, we discuss how local administration of capsaicin may induce ablation of nociceptive terminals and the clinical implications.