| The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels. | |
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MedLine Citation:
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PMID: 18923087 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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The novel endocannabinoid-like lipid N-arachidonoyl L-serine (ARA-S) causes vasodilation through both endothelium-dependent and -independent mechanisms. We have analyzed the vasorelaxant effect of ARA-S in isolated vascular preparations and its effects on Ca(2+)-activated K(+) currents in human embryonic kidney cells stably transfected with the alpha-subunit of the human, large conductance Ca(+)-activated K(+) (BK(Ca)) channel [human embryonic kidney (HEK) 293hSlo cells]. ARA-S caused relaxation of rat isolated, intact and denuded, small mesenteric arteries preconstricted with (R)-(-)-1-(3-hydroxyphenyl)-2-methylaminoethanol hydrochloride (pEC(50), 5.49 and 5.14, respectively), whereas it caused further contraction of vessels preconstricted with KCl (pEC(50), 5.48 and 4.82, respectively). Vasorelaxation by ARA-S was inhibited by 100 nM iberiotoxin. In human embryonic kidney cells stably transfected with the alpha-subunit of the human BK(Ca) channel cells, ARA-S and its enantiomer, N-arachidonoyl-D-serine, enhanced the whole-cell outward K(+) current with similar potency (pEC(50), 5.63 and 5.32, respectively). The potentiation was not altered by the beta(1) subunit or mediated by ARA-S metabolites, stimulation of known cannabinoid receptors, G proteins, protein kinases, or Ca(2+)-dependent processes; it was lost after patch excision or after membrane cholesterol depletion but was restored after cholesterol reconstitution. BK(Ca) currents were also enhanced by N-arachidonoyl ethanolamide (pEC(50), 5.27) but inhibited by another endocannabinoid, O-arachidonoyl ethanolamine (pIC(50), 6.35), or by the synthetic cannabinoid O-1918 [(-)-1,3-dimethoxy-2-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol] (pIC(50), 6.59), which blocks ARA-S-induced vasodilation. We conclude the following. 1) ARA-S directly activates BK(Ca) channels. 2) This interaction does not involve cannabinoid receptors or cytosolic factors but is dependent on the presence of membrane cholesterol. 3) Direct BK(Ca) channel activation probably contributes to the endothelium-independent component of ARA-S-induced mesenteric vasorelaxation. 4) O-1918 is a BK(Ca) channel inhibitor. |
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Authors:
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Grzegorz Godlewski; László Offertáler; Douglas Osei-Hyiaman; Fong Ming Mo; Judith Harvey-White; Jie Liu; Margaret I Davis; Li Zhang; Raj K Razdan; Garry Milman; Pal Pacher; Partha Mukhopadhyay; David M Lovinger; George Kunos |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Intramural Date: 2008-10-15 |
Journal Detail:
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Title: The Journal of pharmacology and experimental therapeutics Volume: 328 ISSN: 1521-0103 ISO Abbreviation: J. Pharmacol. Exp. Ther. Publication Date: 2009 Jan |
Date Detail:
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Created Date: 2008-12-19 Completed Date: 2009-02-03 Revised Date: 2012-03-07 |
Medline Journal Info:
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Nlm Unique ID: 0376362 Medline TA: J Pharmacol Exp Ther Country: United States |
Other Details:
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Languages: eng Pagination: 351-61 Citation Subset: IM |
Affiliation:
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Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892-9413, USA. godlewskig@mail.nih.gov |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Alternative Splicing Animals Arachidonic Acids / physiology* Brain / physiology* Cell Line Genetic Variation Humans Kidney / enzymology Large-Conductance Calcium-Activated Potassium Channels / genetics, physiology* Male Membrane Potentials / physiology Patch-Clamp Techniques Rats Rats, Sprague-Dawley Serine / analogs & derivatives*, physiology |
| Grant Support | |
ID/Acronym/Agency:
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Z01 AA000375-02/AA/NIAAA NIH HHS; Z99 AA999999/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Arachidonic Acids; 0/Large-Conductance Calcium-Activated Potassium Channels; 0/N-arachidonoyl L-serine; 56-45-1/Serine |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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