Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors
BACKGROUND: Trace amines, such as tyramine, are endogenous amino acid metabolites that have been hypothesized to promote headache. However, the underlying cellular and molecular mechanisms remain unknown. METHODS: Using patch-clamp recording, immunostaining, molecular biological approaches and behav...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Springer Milan
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165857/ https://www.ncbi.nlm.nih.gov/pubmed/37158881 http://dx.doi.org/10.1186/s10194-023-01582-5 |
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author | Zhang, Yuan Wang, Hua Sun, Yufang Huang, Zitong Tao, Yu Wang, Yiru Jiang, Xinghong Tao, Jin |
author_facet | Zhang, Yuan Wang, Hua Sun, Yufang Huang, Zitong Tao, Yu Wang, Yiru Jiang, Xinghong Tao, Jin |
author_sort | Zhang, Yuan |
collection | PubMed |
description | BACKGROUND: Trace amines, such as tyramine, are endogenous amino acid metabolites that have been hypothesized to promote headache. However, the underlying cellular and molecular mechanisms remain unknown. METHODS: Using patch-clamp recording, immunostaining, molecular biological approaches and behaviour tests, we elucidated a critically functional role of tyramine in regulating membrane excitability and pain sensitivity by manipulating Kv1.4 channels in trigeminal ganglion (TG) neurons. RESULTS: Application of tyramine to TG neurons decreased the A-type K(+) current (I(A)) in a manner dependent on trace amine-associated receptor 1 (TAAR1). Either siRNA knockdown of Gαo or chemical inhibition of βγ subunit (G(βγ)) signaling abrogated the response to tyramine. Antagonism of protein kinase C (PKC) prevented the tyramine-induced I(A) response, while inhibition of conventional PKC isoforms or protein kinase A elicited no such effect. Tyramine increased the membrane abundance of PKC(θ) in TG neurons, and either pharmacological or genetic inhibition of PKC(θ) blocked the TAAR1-mediated I(A) decrease. Furthermore, PKC(θ)-dependent I(A) suppression was mediated by Kv1.4 channels. Knockdown of Kv1.4 abrogated the TAAR1-induced I(A) decrease, neuronal hyperexcitability, and pain hypersensitivity. In a mouse model of migraine induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus, blockade of TAAR1 signaling attenuated mechanical allodynia; this effect was occluded by lentiviral overexpression of Kv1.4 in TG neurons. CONCLUSION: These results suggest that tyramine induces Kv1.4-mediated I(A) suppression through stimulation of TAAR1 coupled to the G(βγ)-dependent PKC(θ) signaling cascade, thereby enhancing TG neuronal excitability and mechanical pain sensitivity. Insight into TAAR1 signaling in sensory neurons provides attractive targets for the treatment of headache disorders such as migraine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-023-01582-5. |
format | Online Article Text |
id | pubmed-10165857 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Springer Milan |
record_format | MEDLINE/PubMed |
spelling | pubmed-101658572023-05-09 Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors Zhang, Yuan Wang, Hua Sun, Yufang Huang, Zitong Tao, Yu Wang, Yiru Jiang, Xinghong Tao, Jin J Headache Pain Research BACKGROUND: Trace amines, such as tyramine, are endogenous amino acid metabolites that have been hypothesized to promote headache. However, the underlying cellular and molecular mechanisms remain unknown. METHODS: Using patch-clamp recording, immunostaining, molecular biological approaches and behaviour tests, we elucidated a critically functional role of tyramine in regulating membrane excitability and pain sensitivity by manipulating Kv1.4 channels in trigeminal ganglion (TG) neurons. RESULTS: Application of tyramine to TG neurons decreased the A-type K(+) current (I(A)) in a manner dependent on trace amine-associated receptor 1 (TAAR1). Either siRNA knockdown of Gαo or chemical inhibition of βγ subunit (G(βγ)) signaling abrogated the response to tyramine. Antagonism of protein kinase C (PKC) prevented the tyramine-induced I(A) response, while inhibition of conventional PKC isoforms or protein kinase A elicited no such effect. Tyramine increased the membrane abundance of PKC(θ) in TG neurons, and either pharmacological or genetic inhibition of PKC(θ) blocked the TAAR1-mediated I(A) decrease. Furthermore, PKC(θ)-dependent I(A) suppression was mediated by Kv1.4 channels. Knockdown of Kv1.4 abrogated the TAAR1-induced I(A) decrease, neuronal hyperexcitability, and pain hypersensitivity. In a mouse model of migraine induced by electrical stimulation of the dura mater surrounding the superior sagittal sinus, blockade of TAAR1 signaling attenuated mechanical allodynia; this effect was occluded by lentiviral overexpression of Kv1.4 in TG neurons. CONCLUSION: These results suggest that tyramine induces Kv1.4-mediated I(A) suppression through stimulation of TAAR1 coupled to the G(βγ)-dependent PKC(θ) signaling cascade, thereby enhancing TG neuronal excitability and mechanical pain sensitivity. Insight into TAAR1 signaling in sensory neurons provides attractive targets for the treatment of headache disorders such as migraine. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10194-023-01582-5. Springer Milan 2023-05-08 /pmc/articles/PMC10165857/ /pubmed/37158881 http://dx.doi.org/10.1186/s10194-023-01582-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhang, Yuan Wang, Hua Sun, Yufang Huang, Zitong Tao, Yu Wang, Yiru Jiang, Xinghong Tao, Jin Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
title | Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
title_full | Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
title_fullStr | Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
title_full_unstemmed | Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
title_short | Trace amine-associated receptor 1 regulation of Kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
title_sort | trace amine-associated receptor 1 regulation of kv1.4 channels in trigeminal ganglion neurons contributes to nociceptive behaviors |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10165857/ https://www.ncbi.nlm.nih.gov/pubmed/37158881 http://dx.doi.org/10.1186/s10194-023-01582-5 |
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