Irreversible temperature gating in trpv1 sheds light on channel activation

Sánchez-Moreno, Ana; Guevara-Hernández, Eduardo; Contreras-Cervera, Ricardo; Rangel‐Yescas, Gisela E.; Ladrón‐de‐Guevara, Ernesto; Rosenbaum, Tamara; Islas, León D

doi:10.1101/251124

Cited by 13 publications

(26 citation statements)

References 48 publications

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“…An important observation is the fact that this structure is not reversible. In accordance with this, we have recently shown that temperature-dependent gating of full length TRPV1 is also irreversible and this irreversibility is reflected in a large hysteresis during the activation processes (49). It is thus possible that the behavior of the ARD observed here could be related to this irreversible gating process.…”

Section: Discussionsupporting

confidence: 65%

The contribution of the ankyrin repeat domain of TRPV1 as a thermal module

Ladrón‐de‐Guevara

Rangel‐Yescas

Fernández‐Velasco

et al. 2019

Preprint

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11The TRPV1 cation non-selective ion channel plays an essential role in thermosensation and perception of 12 other noxious stimuli. TRPV1 can be activated by low pH, high temperature or naturally occurring 13 pungent molecules such as allicin, capsaicin or resiniferatoxin. Its noxious thermal sensitivity makes it an 14 important participant as a thermal sensor in mammals. However, details of the mechanism of channel 15 activation by increases in temperature remain unclear. Here we used a combination of approaches to try 16 to understand the role of the ankyrin repeat domain (ARD) in channel behavior. First, a computational 17 modeling approach by coarse-grained molecular dynamics simulation of the whole TRPV1 embedded in 18 a phosphatidylcholine (POPC) and phosphatidylethanolamine (POPE) membrane provides insight into 19 the dynamics of this channel domain. Global analysis of the structural ensemble shows that the ankyrin 20 repeat domain is a region that sustains high fluctuations during dynamics at different temperatures. We 21 then performed biochemical and thermal stability studies of the purified ARD by means of circular 22 dichroism and tryptophan fluorescence and demonstrate that this region undergoes structural changes 23 at similar temperatures that lead to TRPV1 activation. Our data suggest that the ARD is a dynamic 24 module and that it may participate in controlling the temperature sensitivity of TRPV1. 25 Statement of Significance 26This work demonstrates that the temperature-dependent dynamics of the ankyrin repeat domain (ARD) 27 of TRPV1 channels, as probed by coarse-grained molecular dynamics, corresponds to the experimentally 28 determined dynamics of an isolated ARD domain. These results show that this region of TRPV1 channels 29 undergoes significant conformational change as a function of increased temperature and suggest that it 30 participates in the temperature-dependent structural changes that lead to channel opening. 31

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Section: Discussionsupporting

confidence: 65%

The contribution of the ankyrin repeat domain of TRPV1 as a thermal module

Ladrón‐de‐Guevara

Rangel‐Yescas

Fernández‐Velasco

et al. 2019

Preprint

Self Cite

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“… 30 , 31 The reason for the prolonged pain relief is not clear but may be related to established research that shows pulsed heat at certain temperatures can result in prolonged deactivation of TRPV1 calcium channels. 32 While that research was not done on humans, it is known that capsaicin, a selective TRPV1 channel agent, can cause prolonged desensitization and inactivation of the TRPV1 channel. 33 , 34 In addition, some of the prolonged TRPV1 response may be secondary to change occurring in the dorsal horn or central nervous system as prolonged effects can sometimes be noted with acupuncture like TENS causing a sustained effect that can be reversed by naloxone.…”

Section: Discussionmentioning

confidence: 99%

The Effectiveness of Thermal Neuromodulation Using Precise Heat in the Treatment of Chronic Low Back Pain Over 60 Days: An In-Home User Trial

Hapgood¹,

Chabal²,

Dunbar³

2021

JPR

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Purpose: Two previous independent double-blind randomized studies demonstrated that thermal neuromodulation using high temperature pulsed heat reduced pain in subjects with chronic low back pain. The present study examined the effects of high temperature pulsed heat via an experimental device in a real-world In-Home Use Trial (IHUT) over a sixty-day period. Materials and Methods: This in-home study recruited 34 subjects with chronic low back pain, provided them with an experimental device that delivered treatment session of high temperature pulsed heat up to 45°C, and followed them for eight weeks. Subjects were allowed to use the device as needed. Primary outcome was pain rating as measured by the 11-point Numeric Pain Scale at baseline, four and eight weeks of treatment. The secondary outcome measures were the interference with daily living components of the Brief Pain Inventory at baseline versus eight weeks of treatment. Results: Thirty-two subjects completed the study. Pain levels were 5.81 at baseline, 2.79 at four weeks and 2.25 at eight weeks. All changes in pain levels between baseline and four weeks, baseline, and eight weeks and between four and eight weeks were statistically significant (p < 0.05). At eight weeks, the seven components of pain interference with activities of daily living and pain interference with walking were statistically reduced (P < 0.05). About 72% of subjects reported a single 30-minute treatment session produced over 3 hours of pain relief. Conclusion:An eight-week in-home trial of high-temperature thermal modulation devices produced significant reductions in pain and pain interference with activities of daily living, an important measure of function. Efforts were made to control and reduce study contamination. This study provides important initial data for long-term outcome studies of thermal neuromodulation using high temperature pulsed heat to treat low back pain and to improve subject function and demonstrated that individuals with chronic pain can effectively selfmanage pain.

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“…Because of the relatively slow speed (on the second timescale) of preheated solution perfusion to achieve temperature jumps, heat-induced desensitization of TRP channels 18,[26][27][28] could largely affect our measurement of heat-activated threshold. Therefore, we used a laser-based experimental setup for the photothermal effects to achieve rapid heating 16,29 on the cell membranes expressing MrTRPA1 and MrTRPV1 within milliseconds.…”

Section: Heat-activated Thresholds Of Mrtrpa1 and Mrtrpv1mentioning

confidence: 99%

Molecular sensors for temperature detection during behavioral thermoregulation in turtle embryos

Zhang

et al. 2021

Current Biology

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Irreversible temperature gating in trpv1 sheds light on channel activation

Cited by 13 publications

References 48 publications

The contribution of the ankyrin repeat domain of TRPV1 as a thermal module

The contribution of the ankyrin repeat domain of TRPV1 as a thermal module

The Effectiveness of Thermal Neuromodulation Using Precise Heat in the Treatment of Chronic Low Back Pain Over 60 Days: An In-Home User Trial

Molecular sensors for temperature detection during behavioral thermoregulation in turtle embryos

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