The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels.
The endogenous brain constituent N-arachidonoyl L-serine is an activator of large conductance Ca2+-activated K+ channels.
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DOI：
10.1124/jpet.108.144717
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发表时间：
2009-01
影响因子：
3.5
通讯作者：
Kunos, George
中科院分区：
文献类型：
--
作者：
Godlewski, Grzegorz;Offertaler, Laszlo;Osei-Hyiaman, Douglas;Mo, Fong Ming;Harvey-White, Judith;Liu, Jie;Davis, Margaret I.;Zhang, Li;Razdan, Raj K.;Milman, Garry;Pacher, Pal;Mukhopadhyay, Partha;Lovinger, David M.;Kunos, George
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 Ca2+-activated K+ currents in human embryonic kidney cells stably transfected with the α-subunit of the human, large conductance Ca+-activated K+ (BKCa) channel (HEK293hSlo cells). ARA-S caused relaxation of rat isolated, intact and denuded, small mesenteric arteries pre-constricted with phenylephrine (pEC50: 5.49 and 5.14, respectively), whereas it caused further contraction of vessels pre-constricted with KCl (pEC50 5.48 and 4.82, respectively). Vasorelaxation by ARA-S was inhibited by 100 nM iberiotoxin. In HEK293hSlo cells, ARA-S and its enantiomer N-arachidonoyl-D-serine enhanced the whole cell outward K+ current with similar potency (pEC50: 5.63 and 5.32, respectively). The potentiation was not altered by β1 subunit or mediated by ARA-S metabolites, stimulation of known cannabinoid receptors, G proteins, protein kinases or Ca2+-dependent processes; it was lost after patch excision or following membrane cholesterol depletion, but was restored after cholesterol reconstitution. BKCa currents were also enhanced by anandamide (pEC50: 5.27) but inhibited by another endocannabinoid, virodhamine (pIC50: 6.35), or by the synthetic cannabinoid O-1918 (pIC50: 6.59), which blocks ARA-S-induced vasodilation. We conclude that (i) ARA-S directly activates BKCa channels. (ii) This interaction does not involve cannabinoid receptors or cytosolic factors but is dependent on the presence of membrane cholesterol. (iii) Direct BKCa channel activation likely contributes to the endothelium-independent component of ARA-S-induced mesenteric vasorelaxation. (iv) O-1918 is a BKCa channel inhibitor.
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影响因子：
2.4
作者：
Connell, Robert J. O.;Yuan, Chunbo;Treistman, Steven N.
通讯作者：
Treistman, Steven N.
影响因子：
4.7
作者：
Duerson, K;White, RE;Armstrong, DL
通讯作者：
Armstrong, DL
影响因子：
8.3
作者：
Gauthier, KM;Edwards, EM;Campbell, WB
通讯作者：
Campbell, WB
影响因子：
3.6
作者：
O'Malley, D;Harvey, J
通讯作者：
Harvey, J
影响因子：
7.3
作者：
Plane, F;Holland, M;Boyle, JP
通讯作者：
Boyle, JP