title: Sensitization of cardiac Ca²⁺ release sites by protein kinase C signaling: evidence from action of murrayafoline A.
abstract: In the present study, we explored the effects of a plant alkaloid compound, 1-methoxy-3-methylcarbazole (murrayafoline A, Mu-A), on focal and global Ca(2+) signaling, and the underlying cellular mechanisms. Rapid two-dimensional confocal Ca(2+) imaging and image analysis were used to measure Ca(2+) signals in rat ventricular myocytes. Application of Mu-A (10-100 μM) significantly enhanced the magnitude and rate of Ca(2+) release on depolarization with no change in Ca(2+) transient decay. Focal Ca(2+) release events (Ca(2+) sparks) occurred more often, and their duration and size were greater after the application of Mu-A. In addition, sarcoplasmic reticulum (SR) Ca(2+) loading and fractional release were increased by exposure to Mu-A. All these effects reached steady state within 2-3 min after Mu-A application. The higher occurrence of Ca(2+) sparks in the presence of Mu-A was resistant to SR Ca(2+) clamping, removal of extracellular Ca(2+) and Na(+), and blockade of either protein kinase A, Ca(2+)/calmodulin-dependent protein kinase II, phospholipase C, or inositol 1,4,5-trisphosphate receptors, but it was abolished by the inhibition of protein kinase C (PKC). SR Ca(2+) clamping prevented the Mu-A-induced Ca(2+) spark prolongation and enlargement. The Mu-A-induced enhancement of Ca(2+) transients was also eliminated by PKC blockade. Mu-A enhanced PKC activity in vitro. These results suggest that Mu-A may increase spark occurrence via its direct enhancement of PKC activity and subsequent sensitization of ryanodine receptor clusters and that this mechanism, as well as increased SR Ca(2+) loading, may partly explain larger and more rapid global Ca(2+) releases in the presence of Mu-A during depolarization.
authors.affiliation: Laboratory of Physiology, College of Pharmacy, Chungnam National University, 220 Gungdong, Yuseong-gu, Daejeon, 305-764, South Korea.
authors.forename: Joon-Chul
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Laboratory of Physiology, College of Pharmacy, Chungnam National University, 220 Gungdong, Yuseong-gu, Daejeon, 305-764, South Korea.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Laboratory of Physiology, College of Pharmacy, Chungnam National University, 220 Gungdong, Yuseong-gu, Daejeon, 305-764, South Korea.
authors.forename: Min-Jung
authors.initials: MJ
authors.lastname: Son
authors.affiliation: Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, Hanoi, Vietnam.
authors.forename: Nguyen Manh
authors.initials: NM
authors.lastname: Cuong
authors.affiliation: Laboratory of Physiology, College of Pharmacy, Chungnam National University, 220 Gungdong, Yuseong-gu, Daejeon, 305-764, South Korea. shwoo@cnu.ac.kr.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Woo
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D002478:Cells, Cultured; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D000470:Alkaloids; D002227:Carbazoles; D053496:Inositol 1,4,5-Trisphosphate Receptors; C443728:murrayafoline A; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D010738:Type C Phospholipases
references.citation: J Physiol. 1988 Nov;405:233-55
references.pmid: 2475607
references.citation: J Physiol. 1997 Apr 15;500 ( Pt 2):297-309
references.pmid: 9147318
references.citation: J Physiol. 2010 Jan 1;588(Pt 1):225-42
references.pmid: 19900959
references.citation: Science. 1993 Oct 29;262(5134):740-4
references.pmid: 8235594
references.citation: Science. 1989 May 19;244(4906):800-3
references.pmid: 2543067
references.citation: Physiol Rev. 2008 Oct;88(4):1491-545
references.pmid: 18923188
references.citation: J Biol Chem. 1984 Jul 10;259(13):8029-32
references.pmid: 6234308
references.citation: Am J Physiol. 1997 Dec;273(6):C2090-5
references.pmid: 9435516
references.citation: J Pharmacol Exp Ther. 2009 May;329(2):532-42
references.pmid: 19190235
references.citation: Am J Physiol. 1997 Feb;272(2 Pt 2):H657-68
references.pmid: 9124422
references.citation: Circ Res. 2005 Jun 24;96(12):1274-81
references.pmid: 15933266
references.citation: J Physiol. 2002 Sep 1;543(Pt 2):439-53
references.pmid: 12205180
references.citation: Cardiovasc Res. 2012 Jul 1;95(1):59-68
references.pmid: 22617407
references.citation: Biophys J. 1994 Nov;67(5):1942-56
references.pmid: 7858131
references.citation: Prog Biophys Mol Biol. 2010 Sep;103(1):59-70
references.pmid: 20193706
references.citation: Ann Pharmacother. 2006 Jan;40(1):53-7
references.pmid: 16317106
references.citation: Biochemistry. 1993 Mar 23;32(11):2923-30
references.pmid: 8384482
references.citation: J Physiol. 1994 Nov 1;480 ( Pt 3):411-21
references.pmid: 7869256
references.citation: Am J Physiol. 1995 Feb;268(2 Pt 2):H916-20
references.pmid: 7864219
references.citation: J Membr Biol. 1997 Oct 1;159(3):179-85
references.pmid: 9312207
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10984-9
references.pmid: 9724816
references.citation: Cardiovasc Res. 2002 Mar;53(4):782-805
references.pmid: 11922890
references.citation: J Asian Nat Prod Res. 2002 Dec;4(4):233-41
references.pmid: 12450250
references.citation: Science. 1990 Oct 26;250(4980):565-8
references.pmid: 2173135
references.citation: J Physiol. 2002 Jun 1;541(Pt 2):395-409
references.pmid: 12042347
references.citation: Chem Pharm Bull (Tokyo). 2004 Oct;52(10):1175-8
references.pmid: 15467229
references.citation: Am J Physiol. 1995 May;268(5 Pt 1):C1313-9
references.pmid: 7762626
references.citation: J Physiol. 2007 Sep 1;583(Pt 2):685-94
references.pmid: 17599964
references.citation: J Membr Biol. 2011 Mar;240(1):21-33
references.pmid: 21274522
references.citation: Circ Res. 2003 Jan 10;92(1):e1-11
references.pmid: 12522129
references.citation: J Physiol. 1991 Jan;432:283-312
references.pmid: 1653321
references.citation: J Physiol. 1995 Sep 15;487 ( Pt 3):601-8
references.pmid: 8544124
references.citation: Am J Med. 2007 Jan;120(1):e19; author reply e21
references.pmid: 17208064
references.citation: J Physiol. 2000 Jan 15;522 Pt 2:259-70
references.pmid: 10639102
references.citation: Biochem Biophys Res Commun. 2010 Jan 1;391(1):915-20
references.pmid: 19962966
references.citation: Annu Rev Physiol. 1994;56:485-508
references.pmid: 7516645
references.citation: J Biochem. 1991 Jan;109(1):163-70
references.pmid: 1849885
references.citation: Cell Calcium. 2011 Feb;49(2):136-43
references.pmid: 21241999
references.citation: Eur J Pharmacol. 1989 Oct 4;169(1):137-45
references.pmid: 2599008
references.citation: J Biol Chem. 1997 Oct 3;272(40):25333-8
references.pmid: 9312152
references.citation: Am J Respir Cell Mol Biol. 2009 Jun;40(6):663-71
references.pmid: 19011160
references.citation: Proc Natl Acad Sci U S A. 2009 Oct 20;106(42):18028-33
references.pmid: 19815510
references.citation: J Gen Physiol. 2003 Oct;122(4):407-17
references.pmid: 12975450
references.citation: Nature. 1988 Sep 15;335(6187):249-51
references.pmid: 2457814
references.citation: Planta Med. 2001 Apr;67(3):244-8
references.pmid: 11345696
references.citation: J Nat Prod. 2000 Jul;63(7):893-7
references.pmid: 10924160
references.citation: Biophys J. 1998 Dec;75(6):2801-10
references.pmid: 9826602
references.citation: Cell. 2000 May 12;101(4):365-76
references.pmid: 10830164
references.citation: Circ Res. 1998 Dec 14-28;83(12):1192-204
references.pmid: 9851936
references.citation: Curr Mol Med. 2012 Feb;12(2):206-17
references.pmid: 22280358
references.citation: J Biol Chem. 1983 Jan 10;258(1):464-71
references.pmid: 6217205
references.citation: J Physiol. 1996 Oct 15;496 ( Pt 2):575-81
references.pmid: 8910239