Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels.
(+)-SKF 10047 (N-allyl-normetazocine) is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+)-SKF 10047 inhibits K(+), Na(+) and Ca2+ channels via sigma-1 receptor activation. We found that (+)-SKF 10047 inhibited Na(V)1.2...
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2012-01-01
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doaj-0b4c76f935d04c589a2363160d71ad862020-11-25T02:48:02ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01711e4938410.1371/journal.pone.0049384Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels.Xiao-Fei GaoJin-Jing YaoYan-Lin HeChanglong HuYan-Ai Mei(+)-SKF 10047 (N-allyl-normetazocine) is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+)-SKF 10047 inhibits K(+), Na(+) and Ca2+ channels via sigma-1 receptor activation. We found that (+)-SKF 10047 inhibited Na(V)1.2 and Na(V)1.4 channels independently of sigma-1 receptor activation. (+)-SKF 10047 equally inhibited Na(V)1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in COS-7 cells, which barely express sigma-1 receptors. The sigma-1 receptor antagonists BD 1063,BD 1047 and NE-100 did not block the inhibitory effects of (+)-SKF-10047. Blocking of the PKA, PKC and G-protein pathways did not affect (+)-SKF 10047 inhibition of Na(V)1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and 1,3-di-o-tolyl-guanidine (DTG) also inhibited Na(V)1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of Na(V)1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe(1764) and Tyr(1771) in the IV-segment 6 domain of the Na(V)1.2 channel and Phe(1579) in the Na(V)1.4 channel for (+)-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit Na(V)1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies.http://europepmc.org/articles/PMC3489664?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Xiao-Fei Gao Jin-Jing Yao Yan-Lin He Changlong Hu Yan-Ai Mei |
spellingShingle |
Xiao-Fei Gao Jin-Jing Yao Yan-Lin He Changlong Hu Yan-Ai Mei Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. PLoS ONE |
author_facet |
Xiao-Fei Gao Jin-Jing Yao Yan-Lin He Changlong Hu Yan-Ai Mei |
author_sort |
Xiao-Fei Gao |
title |
Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. |
title_short |
Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. |
title_full |
Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. |
title_fullStr |
Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. |
title_full_unstemmed |
Sigma-1 receptor agonists directly inhibit Nav1.2/1.4 channels. |
title_sort |
sigma-1 receptor agonists directly inhibit nav1.2/1.4 channels. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS ONE |
issn |
1932-6203 |
publishDate |
2012-01-01 |
description |
(+)-SKF 10047 (N-allyl-normetazocine) is a prototypic and specific sigma-1 receptor agonist that has been used extensively to study the function of sigma-1 receptors. (+)-SKF 10047 inhibits K(+), Na(+) and Ca2+ channels via sigma-1 receptor activation. We found that (+)-SKF 10047 inhibited Na(V)1.2 and Na(V)1.4 channels independently of sigma-1 receptor activation. (+)-SKF 10047 equally inhibited Na(V)1.2/1.4 channel currents in HEK293T cells with abundant sigma-1 receptor expression and in COS-7 cells, which barely express sigma-1 receptors. The sigma-1 receptor antagonists BD 1063,BD 1047 and NE-100 did not block the inhibitory effects of (+)-SKF-10047. Blocking of the PKA, PKC and G-protein pathways did not affect (+)-SKF 10047 inhibition of Na(V)1.2 channel currents. The sigma-1 receptor agonists Dextromethorphan (DM) and 1,3-di-o-tolyl-guanidine (DTG) also inhibited Na(V)1.2 currents through a sigma-1 receptor-independent pathway. The (+)-SKF 10047 inhibition of Na(V)1.2 currents was use- and frequency-dependent. Point mutations demonstrated the importance of Phe(1764) and Tyr(1771) in the IV-segment 6 domain of the Na(V)1.2 channel and Phe(1579) in the Na(V)1.4 channel for (+)-SKF 10047 inhibition. In conclusion, our results suggest that sigma-1 receptor agonists directly inhibit Na(V)1.2/1.4 channels and that these interactions should be given special attention for future sigma-1 receptor function studies. |
url |
http://europepmc.org/articles/PMC3489664?pdf=render |
work_keys_str_mv |
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