Research article summary (published 19 Oct 2009):

T-type calcium channel inhibition underlies the analgesic effects of the endogenous lipoamino acids.

Full Abstract

Lipoamino acids are anandamide-related endogenous molecules that induce analgesia via unresolved mechanisms. Here, we provide evidence that the T-type/Cav3 calcium channels are important pharmacological targets underlying their physiological effects. Various lipoamino acids, including N-arachidonoyl glycine (NAGly), reversibly inhibited Cav3.1, Cav3.2, and Cav3.3 currents, with potent effects on Cav3.2 [EC(50) approximately 200 nm for N-arachidonoyl 3-OH-gamma-aminobutyric acid (NAGABA-OH)]. This inhibition involved a large shift in the Cav3.2 steady-state inactivation and persisted during fatty acid amide hydrolase (FAAH) inhibition as well as in cell-free outside-out patch. In contrast, lipoamino acids had weak effects on high-voltage-activated (HVA) Cav1.2 and Cav2.2 calcium currents, on Nav1.7 and Nav1.8 sodium currents, and on anandamide-sensitive TRPV1 and TASK1 currents. Accordingly, lipoamino acids strongly inhibited native Cav3.2 currents in sensory neurons with small effects on sodium and HVA calcium currents. In addition, we demonstrate here that lipoamino acids NAGly and NAGABA-OH produced a strong thermal analgesia and that these effects (but not those of morphine) were abolished in Cav3.2 knock-out mice. Collectively, our data revealed lipoamino acids as a family of endogenous T-type channel inhibitors, suggesting that these ligands can modulate multiple cell functions via this newly evidenced regulation.

Author information

Author/s: Barbara, Guillaume (G); Alloui, Abdelkrim (A); Nargeot, Joël (J); Lory, Philippe (P); Eschalier, Alain (A); Bourinet, Emmanuel (E); Chemin, Jean (J);

Affiliation: Département de Physiologie, Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique Unité Mixte de Recherche 5203, INSERM U661, Universités de Montpellier, 34094 Montpellier, France.

Journal and publication information

Publication Type: Journal Article; Research Support, Non-U.S. Gov't

Journal: The Journal of neuroscience : the official journal of the Society for Neuroscience (J Neurosci), published in United States. (Language: eng)

Reference: 2009-Oct; vol 29 (issue 42) : pp 13106-14

Dates: Created 2009/10/22; Completed 2009/11/06;

PMID: 19846698, status: MEDLINE (last retrieval date: 11/6/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

External Links for this article
(including full text providers, if available):

Click Electronic Full-text Provider Links to see options for finding the electronic full text links to this article. Note there may be a subscription or fee required for access to the full text. See our FAQ for information on finding FREE full text articles.

This article may also be located in paper journal collections available in many libraries. Use the Journal and Publication Information above to find the full article.

MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Analgesics - pharmacology Animals Arachidonic Acids - pharmacology Behavior, Animal - physiology Calcium - metabolism Calcium Channel Blockers - pharmacology Calcium Channels, L-Type - genetics Calcium Channels, T-Type - classification; genetics; metabolism Cells, Cultured Disease Models, Animal Electric Stimulation - methods Ganglia, Spinal - cytology Glycine - analogs & derivatives; pharmacology Green Fluorescent Proteins - genetics Humans Hyperalgesia - drug therapy; genetics

Hyperalgesia - drug therapy; genetics Male Membrane Potentials - drug effects; genetics Mice Mice, Inbred C57BL Mice, Knockout Morphine - pharmacology Nerve Tissue Proteins - genetics Neuroblastoma Patch-Clamp Techniques - methods Potassium Channels, Tandem Pore Domain - genetics Sensory Receptor Cells Sodium Channels - genetics TRPV Cation Channels - genetics Transfection gamma-Aminobutyric Acid - analogs & derivatives; pharmacology

Associated Chemicals: Analgesics (0) ; Arachidonic Acids (0) ; Calcium Channel Blockers (0) ; Calcium Channels, L-Type (0) ; Calcium Channels, T-Type (0) ; N-arachidonoyl-gamma-amino-butyric acid (0) ; N-arachidonylglycine (0) ; Nerve Tissue Proteins (0) ; Potassium Channels, Tandem Pore Domain (0) ; SCN9A protein, human (0) ; Sodium Channels (0) ; TRPV Cation Channels (0) ; TRPV1 protein, human (0) ; potassium channel subfamily K member 3 (0) ; Green Fluorescent Proteins (147336-22-9) ; gamma-Aminobutyric Acid (56-12-2) ; Glycine (56-40-6) ; Morphine (57-27-2) ; Calcium (7440-70-2)

Related articles

These are the highest related articles currently in the database:

• The Cav3.2/alpha1H T-type Ca2+ current is a molecular determinant of excitatory effects of GABA in adult sensory neurons. 22 Jul 2007
• Effects of anandamide and noxious heat on intracellular calcium concentration in nociceptive drg neurons of rats. 18 Jun 2007
• 5beta-reduced neuroactive steroids are novel voltage-dependent blockers of T-type Ca2+ channels in rat sensory neurons in vitro and potent peripheral analgesics in vivo. 25 Jul 2004
• Gabapentin (neurontin) and S-(+)-3-isobutylgaba represent a novel class of selective antihyperalgesic agents. 30 Jul 1997
• Methanandamide activation of a novel current in mouse trigeminal ganglion sensory neurons in vitro. 5 Jun 2007
• Neuronal T-type alpha 1H calcium channels induce neuritogenesis and expression of high-voltage-activated calcium channels in the NG108-15 cell line. 13 Aug 2002
• Identification of N-arachidonylglycine, U18666A, and 4-androstene-3,17-dione as novel insulin Secretagogues. 3 Aug 2005
• Extracellular cations sensitize and gate capsaicin receptor TRPV1 modulating pain signaling. 23 May 2005
• Tetrahydropyridine-4-carboxamides as novel, potent transient receptor potential vanilloid 1 (TRPV1) antagonists. 5 Aug 2008
• The contribution of TWIK-related acid-sensitive K+-containing channels to the function of dorsal lateral geniculate thalamocortical relay neurons. 17 Jan 2006

See 100+ related articles.

Related Article Map

Legend: - FREE Full text Article. - Abstract only. - Title only. More help.

See a large map of 100+ related articles.