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Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation
BACKGROUND AND PURPOSE: The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small‐molecule agonist, but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH: Yoda1 analogues were generated by synthetic chemistry. Intracellu...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913400/ https://www.ncbi.nlm.nih.gov/pubmed/29498036 http://dx.doi.org/10.1111/bph.14188 |
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author | Evans, Elizabeth L Cuthbertson, Kevin Endesh, Naima Rode, Baptiste Blythe, Nicola M Hyman, Adam J Hall, Sally J Gaunt, Hannah J Ludlow, Melanie J Foster, Richard Beech, David J |
author_facet | Evans, Elizabeth L Cuthbertson, Kevin Endesh, Naima Rode, Baptiste Blythe, Nicola M Hyman, Adam J Hall, Sally J Gaunt, Hannah J Ludlow, Melanie J Foster, Richard Beech, David J |
author_sort | Evans, Elizabeth L |
collection | PubMed |
description | BACKGROUND AND PURPOSE: The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small‐molecule agonist, but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH: Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca(2+) and Tl(+) measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta. KEY RESULTS: Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2 μM Yoda1‐induced Ca(2+)‐entry with IC(50)s of 1.3 μM (HEK 293 cells) and 1.5 μM (HUVECs) yet failed to inhibit constitutive Piezo1 channel activity. It had no effect on endogenous ATP‐evoked Ca(2+) elevation or store‐operated Ca(2+) entry in HEK 293 cells or Ca(2+) entry through TRPV4 or TRPC4 channels overexpressed in CHO and HEK 293 cells. Yoda1 caused dose‐dependent relaxation of aortic rings, which was mediated by an endothelium‐ and NO‐dependent mechanism and which was antagonized by Dooku1 and analogues of Dooku1. CONCLUSION AND IMPLICATIONS: Chemical antagonism of Yoda1‐evoked Piezo1 channel activity is possible, and the existence of a specific chemical interaction site is suggested with distinct binding and efficacy domains. |
format | Online Article Text |
id | pubmed-5913400 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-59134002018-04-30 Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation Evans, Elizabeth L Cuthbertson, Kevin Endesh, Naima Rode, Baptiste Blythe, Nicola M Hyman, Adam J Hall, Sally J Gaunt, Hannah J Ludlow, Melanie J Foster, Richard Beech, David J Br J Pharmacol Research Papers BACKGROUND AND PURPOSE: The mechanosensitive Piezo1 channel has important roles in vascular physiology and disease. Yoda1 is a small‐molecule agonist, but the pharmacology of these channels is otherwise limited. EXPERIMENTAL APPROACH: Yoda1 analogues were generated by synthetic chemistry. Intracellular Ca(2+) and Tl(+) measurements were made in HEK 293 or CHO cell lines overexpressing channel subunits and in HUVECs, which natively express Piezo1. Isometric tension recordings were made from rings of mouse thoracic aorta. KEY RESULTS: Modification of the pyrazine ring of Yoda1 yielded an analogue, which lacked agonist activity but reversibly antagonized Yoda1. The analogue is referred to as Dooku1. Dooku1 inhibited 2 μM Yoda1‐induced Ca(2+)‐entry with IC(50)s of 1.3 μM (HEK 293 cells) and 1.5 μM (HUVECs) yet failed to inhibit constitutive Piezo1 channel activity. It had no effect on endogenous ATP‐evoked Ca(2+) elevation or store‐operated Ca(2+) entry in HEK 293 cells or Ca(2+) entry through TRPV4 or TRPC4 channels overexpressed in CHO and HEK 293 cells. Yoda1 caused dose‐dependent relaxation of aortic rings, which was mediated by an endothelium‐ and NO‐dependent mechanism and which was antagonized by Dooku1 and analogues of Dooku1. CONCLUSION AND IMPLICATIONS: Chemical antagonism of Yoda1‐evoked Piezo1 channel activity is possible, and the existence of a specific chemical interaction site is suggested with distinct binding and efficacy domains. John Wiley and Sons Inc. 2018-04-06 2018-05 /pmc/articles/PMC5913400/ /pubmed/29498036 http://dx.doi.org/10.1111/bph.14188 Text en © 2018 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Papers Evans, Elizabeth L Cuthbertson, Kevin Endesh, Naima Rode, Baptiste Blythe, Nicola M Hyman, Adam J Hall, Sally J Gaunt, Hannah J Ludlow, Melanie J Foster, Richard Beech, David J Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation |
title | Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation |
title_full | Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation |
title_fullStr | Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation |
title_full_unstemmed | Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation |
title_short | Yoda1 analogue (Dooku1) which antagonizes Yoda1‐evoked activation of Piezo1 and aortic relaxation |
title_sort | yoda1 analogue (dooku1) which antagonizes yoda1‐evoked activation of piezo1 and aortic relaxation |
topic | Research Papers |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5913400/ https://www.ncbi.nlm.nih.gov/pubmed/29498036 http://dx.doi.org/10.1111/bph.14188 |
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