Direct inhibition of T‐type calcium channels by the endogenous cannabinoid anandamide

Direct inhibition of T‐type calcium channels by the endogenous cannabinoid anandamide Low‐voltage‐activated or T‐type Ca2+ channels (T‐channels) are widely expressed, especially in the central nervous system where they contribute to pacemaker activities and are involved in the pathogenesis of epilepsy. Proper elucidation of their cellular functions has been hampered by the lack of selective pharmacology as well as the absence of generic endogenous regulations. We report here that both cloned (α1G, α1H and α1I subunits) and native T‐channels are blocked by the endogenous cannabinoid, anandamide. Anandamide, known to exert its physiological effects through cannabinoid receptors, inhibits T‐currents independently from the activation of CB1/CB2 receptors, G‐proteins, phospholipases and protein kinase pathways. Anandamide appears to be the first endogenous ligand acting directly on T‐channels at submicromolar concentrations. Block of anandamide membrane transport by AM404 prevents T‐current inhibition, suggesting that anandamide acts intracellularly. Anandamide preferentially binds and stabilizes T‐channels in the inactivated state and is responsible for a significant decrease of T‐currents associated with neuronal firing activities. Our data demonstrate that anandamide inhibition of T‐channels can regulate neuronal excitability and account for CB receptor‐independent effects of this signaling molecule. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The EMBO Journal Wiley

Direct inhibition of T‐type calcium channels by the endogenous cannabinoid anandamide

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Publisher
Wiley
Copyright
Copyright © 2013 Wiley Periodicals, Inc
ISSN
0261-4189
eISSN
1460-2075
DOI
10.1093/emboj/20.24.7033
pmid
11742980
Publisher site
See Article on Publisher Site

Abstract

Low‐voltage‐activated or T‐type Ca2+ channels (T‐channels) are widely expressed, especially in the central nervous system where they contribute to pacemaker activities and are involved in the pathogenesis of epilepsy. Proper elucidation of their cellular functions has been hampered by the lack of selective pharmacology as well as the absence of generic endogenous regulations. We report here that both cloned (α1G, α1H and α1I subunits) and native T‐channels are blocked by the endogenous cannabinoid, anandamide. Anandamide, known to exert its physiological effects through cannabinoid receptors, inhibits T‐currents independently from the activation of CB1/CB2 receptors, G‐proteins, phospholipases and protein kinase pathways. Anandamide appears to be the first endogenous ligand acting directly on T‐channels at submicromolar concentrations. Block of anandamide membrane transport by AM404 prevents T‐current inhibition, suggesting that anandamide acts intracellularly. Anandamide preferentially binds and stabilizes T‐channels in the inactivated state and is responsible for a significant decrease of T‐currents associated with neuronal firing activities. Our data demonstrate that anandamide inhibition of T‐channels can regulate neuronal excitability and account for CB receptor‐independent effects of this signaling molecule.

Journal

The EMBO JournalWiley

Published: May 17, 2002

Keywords: ; ; ; ;

References

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