title: Molecular mechanisms of large-conductance ca (2+) -activated potassium channel activation by ginseng gintonin.
abstract: Gintonin is a unique lysophosphatidic acid (LPA) receptor ligand found in Panax ginseng. Gintonin induces transient [Ca(2+)]i through G protein-coupled LPA receptors. Large-conductance Ca(2+)-activated K(+) (BKCa) channels are expressed in blood vessels and neurons and play important roles in blood vessel relaxation and attenuation of neuronal excitability. BKCa channels are activated by transient [Ca(2+)]i and are regulated by various Ca(2+)-dependent kinases. We investigated the molecular mechanisms of BKCa channel activation by gintonin. BKCa channels are heterologously expressed in Xenopus oocytes. Gintonin treatment induced BKCa channel activation in oocytes expressing the BKCa channel α subunit in a concentration-dependent manner (EC50 = 0.71 ± 0.08 µg/mL). Gintonin-mediated BKCa channel activation was blocked by a PKC inhibitor, calphostin, and by the calmodulin inhibitor, calmidazolium. Site-directed mutations in BKCa channels targeting CaM kinase II or PKC phosphorylation sites but not PKA phosphorylation sites attenuated gintonin action. Mutations in the Ca(2+) bowl and the regulator of K(+) conductance (RCK) site also blocked gintonin action. These results indicate that gintonin-mediated BKCa channel activations are achieved through LPA1 receptor-phospholipase C-IP3-Ca(2+)-PKC-calmodulin-CaM kinase II pathways and calcium binding to the Ca(2+) bowl and RCK domain. Gintonin could be a novel contributor against blood vessel constriction and over-excitation of neurons.
authors: Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine and Bio/Molecular Informatics Center, Konkuk University, Seoul 143-701, Republic of Korea.
authors: S H
authors: SH
authors: Choi
authors: B H
authors: BH
authors: Lee
authors: S H
authors: SH
authors: Hwang
authors: H J
authors: HJ
authors: Kim
authors: S M
authors: SM
authors: Lee
authors: H C
authors: HC
authors: Kim
authors: H W
authors: HW
authors: Rhim
authors: S Y
authors: SY
authors: Nah
references: Mol Pharmacol. 2008 Mar;73(3):619-26
references: 17959711
references: J Neurosci. 2008 Aug 13;28(33):8238-45
references: 18701686
references: Am J Physiol Lung Cell Mol Physiol. 2009 Oct;297(4):L758-66
references: 19592459
references: Neuron. 1995 Mar;14(3):645-50
references: 7695911
references: Nature. 2002 Dec 5;420(6915):499-502
references: 12466841
references: Am J Physiol Renal Physiol. 2000 Aug;279(2):F283-8
references: 10919847
references: Nat Neurosci. 1999 May;2(5):416-21
references: 10321244
references: J Bioenerg Biomembr. 1996 Jun;28(3):255-67
references: 8807400
references: Mol Cells. 2012 Feb;33(2):151-62
references: 22286231
references: J Gen Physiol. 2002 Aug;120(2):173-89
references: 12149279
references: Eur J Pharmacol. 1999 Feb 12;367(1):41-9
references: 10082263
references: Proteins. 2003 Aug 1;52(2):146-54
references: 12833539
references: CNS Drug Rev. 2007 Winter;13(4):381-404
references: 18078425
references: Curr Pharm Des. 2006;12(28):3573-81
references: 17073660
references: News Physiol Sci. 1998 Jun;13:112-117
references: 11390773
references: Nature. 2002 May 30;417(6888):515-22
references: 12037559
references: Nat Rev Neurosci. 2006 Dec;7(12):921-31
references: 17115074
references: Biophys J. 1997 Sep;73(3):1355-63
references: 9284303
references: J Biol Chem. 2001 May 4;276(18):15208-15
references: 11278944
references: Nature. 2002 Aug 22;418(6900):880-4
references: 12192411
references: J Neurosci. 1999 May 15;19(10):RC4
references: 10234050
references: Pflugers Arch. 1990 Apr;416(1-2):7-16
references: 1693768
references: J Smooth Muscle Res. 2004 Oct;40(4-5):125-53
references: 15655302
references: Biol Res. 2006;39(3):385-401
references: 17106573
references: J Physiol. 1997 Aug 1;502 ( Pt 3):545-57
references: 9279807
references: Brain Res Mol Brain Res. 1989 May;5(3):193-202
references: 2471032
references: J Neurosci. 1996 Aug 1;16(15):4543-50
references: 8764643
references: J Gen Physiol. 2005 Mar;125(3):273-86
references: 15738049
references: J Gen Physiol. 2004 May;123(5):475-89
references: 15111643
references: Br J Pharmacol. 2012 Feb;165(4):829-44
references: 21838759
references: Science. 1995 Oct 27;270(5236):633-7
references: 7570021
references: Pflugers Arch. 1989 Mar;413(5):498-504
references: 2472599
references: Acta Pharmacol Sin. 2010 Sep;31(9):1213-22
references: 20729877
references: J Biol Chem. 2002 Jul 5;277(27):24022-9
references: 11980904
references: Mol Cells. 2011 Feb;31(2):133-40
references: 21191818
references: Life Sci. 1995;56(19):1577-86
references: 7723586
references: Pharmacol Ther. 2006 Apr;110(1):103-16
references: 16356551
references: J Neurosci. 2007 Sep 26;27(39):10404-13
references: 17898212
references: J Comp Physiol A Neuroethol Sens Neural Behav Physiol. 2002 Mar;188(2):79-87
references: 11919690
references: J Biol Chem. 1987 Feb 5;262(4):1638-43
references: 3543007
references: Brain Res Mol Brain Res. 1997 Apr;45(1):33-40
references: 9105668
references: J Neurosci. 1997 May 1;17(9):2990-3001
references: 9096135
references: Mol Neurobiol. 2008 Oct;38(2):153-66
references: 18759010
references: J Biol Chem. 1991 Dec 15;266(35):23856-62
references: 1660886
references: Biophys J. 1992 Aug;63(2):583-90
references: 1384740