Cargando…

Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity

The Transient Receptor Potential Vanilloid 1 (TRPV) channel is activated by an array of stimuli, including heat and vanilloid compounds. The TRPV1 homologues TRPV2 and TRPV3 are also activated by heat, but sensitivity to vanilloids and many other agonists is not conserved among TRPV subfamily member...

Descripción completa

Detalles Bibliográficos
Autores principales: Zhang, Feng, Swartz, Kenton Jon, Jara-Oseguera, Andres
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333442/
https://www.ncbi.nlm.nih.gov/pubmed/30644819
http://dx.doi.org/10.7554/eLife.42756
_version_ 1783387563326701568
author Zhang, Feng
Swartz, Kenton Jon
Jara-Oseguera, Andres
author_facet Zhang, Feng
Swartz, Kenton Jon
Jara-Oseguera, Andres
author_sort Zhang, Feng
collection PubMed
description The Transient Receptor Potential Vanilloid 1 (TRPV) channel is activated by an array of stimuli, including heat and vanilloid compounds. The TRPV1 homologues TRPV2 and TRPV3 are also activated by heat, but sensitivity to vanilloids and many other agonists is not conserved among TRPV subfamily members. It was recently discovered that four mutations in TRPV2 are sufficient to render the channel sensitive to the TRPV1-specific vanilloid agonist resiniferatoxin (RTx). Here, we show that mutation of six residues in TRPV3 corresponding to the vanilloid site in TRPV1 is sufficient to engineer RTx binding. However, robust activation of TRPV3 by RTx requires facilitation of channel opening by introducing mutations in the pore, temperatures > 30°C, or sensitization with another agonist. Our results demonstrate that the energetics of channel activation can determine the apparent sensitivity to a stimulus and suggest that allosteric pathways for activation are conserved in the TRPV family.
format Online
Article
Text
id pubmed-6333442
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher eLife Sciences Publications, Ltd
record_format MEDLINE/PubMed
spelling pubmed-63334422019-01-16 Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity Zhang, Feng Swartz, Kenton Jon Jara-Oseguera, Andres eLife Neuroscience The Transient Receptor Potential Vanilloid 1 (TRPV) channel is activated by an array of stimuli, including heat and vanilloid compounds. The TRPV1 homologues TRPV2 and TRPV3 are also activated by heat, but sensitivity to vanilloids and many other agonists is not conserved among TRPV subfamily members. It was recently discovered that four mutations in TRPV2 are sufficient to render the channel sensitive to the TRPV1-specific vanilloid agonist resiniferatoxin (RTx). Here, we show that mutation of six residues in TRPV3 corresponding to the vanilloid site in TRPV1 is sufficient to engineer RTx binding. However, robust activation of TRPV3 by RTx requires facilitation of channel opening by introducing mutations in the pore, temperatures > 30°C, or sensitization with another agonist. Our results demonstrate that the energetics of channel activation can determine the apparent sensitivity to a stimulus and suggest that allosteric pathways for activation are conserved in the TRPV family. eLife Sciences Publications, Ltd 2019-01-15 /pmc/articles/PMC6333442/ /pubmed/30644819 http://dx.doi.org/10.7554/eLife.42756 Text en http://creativecommons.org/publicdomain/zero/1.0/ http://creativecommons.org/publicdomain/zero/1.0/This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication (http://creativecommons.org/publicdomain/zero/1.0/) .
spellingShingle Neuroscience
Zhang, Feng
Swartz, Kenton Jon
Jara-Oseguera, Andres
Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
title Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
title_full Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
title_fullStr Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
title_full_unstemmed Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
title_short Conserved allosteric pathways for activation of TRPV3 revealed through engineering vanilloid-sensitivity
title_sort conserved allosteric pathways for activation of trpv3 revealed through engineering vanilloid-sensitivity
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333442/
https://www.ncbi.nlm.nih.gov/pubmed/30644819
http://dx.doi.org/10.7554/eLife.42756
work_keys_str_mv AT zhangfeng conservedallostericpathwaysforactivationoftrpv3revealedthroughengineeringvanilloidsensitivity
AT swartzkentonjon conservedallostericpathwaysforactivationoftrpv3revealedthroughengineeringvanilloidsensitivity
AT jaraosegueraandres conservedallostericpathwaysforactivationoftrpv3revealedthroughengineeringvanilloidsensitivity