title: Enhancement of contraction and L-type Ca(2+) current by murrayafoline-A via protein kinase C in rat ventricular myocytes.
abstract: We previously reported that murrayafoline-A (1-methoxy-3-methyl-9H-carbazole, Mu-A) increases the contractility of ventricular myocytes, in part, via enhancing Ca(2+) influx through L-type Ca(2+) channels, and that it increases the Ca(2+) transients by activation of protein kinase C (PKC). In the present study, we further examined the cellular mechanisms for the enhancement of contractility and L-type Ca(2+) current (ICa,L) by Mu-A. Cell shortening and ICa,L were measured in rat ventricular myocytes using a video edge detection method and perforated patch-clamp technique, respectively. We found that the positive inotropic effect of Mu-A was not affected by pre-exposure to the β-adrenoceptor antagonist propranolol, the protein kinase A (PKA) inhibitors KT5720 or H-89, or the phospholipase C inhibitor U73122. Interestingly, the Mu-A-mediated increases in cell shortening and in the rate of contraction were completely suppressed by pre-treatment with the PKC inhibitor GF109203X. The stimulatory effect of Mu-A on ICa,L was not altered by inhibition of PKA (KT5720), G-protein coupled receptors (suramin), or α1-adrenoceptor (prazosin). However, pre-exposure to the PKC inhibitor, GF109203X or chelerythrine, abolished the Mu-A-induced increase in ICa,L. Pre-exposure to the Ca(2+)-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93 slightly reduced the stimulatory effects on contraction and ICa,L by Mu-A. Phosphorylation of PKC was enhanced by Mu-A in ventricular myocytes. These data suggest that Mu-A increases contraction and ICa,L via PKC in rat ventricular myocytes, and that the PKC-mediated responses in the presence of Mu-A may be partly mediated by CaMKII.
authors.affiliation: College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.
authors.forename: Bojjibabu
authors.initials: B
authors.lastname: Chidipi
authors.affiliation: College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.
authors.forename: Min-Jeong
authors.initials: MJ
authors.lastname: Son
authors.affiliation: College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea.
authors.forename: Joon-Chul
authors.initials: JC
authors.lastname: Kim
authors.affiliation: Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Jeong Hyun
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Hanoi, Viet Nam.
authors.forename: Tran Quoc
authors.initials: TQ
authors.lastname: Toan
authors.affiliation: Institute of Natural Products Chemistry, Vietnam Academy of Science and Technology, 18 Hoang Quoc Viet Road, Hanoi, Viet Nam.
authors.forename: Nguyen Manh
authors.initials: NM
authors.lastname: Cuong
authors.affiliation: Center for Drug Discovery Technology, Korea Research Institute of Chemical Technology, Daejeon 34114, South Korea.
authors.forename: Byung Ho
authors.initials: BH
authors.lastname: Lee
authors.affiliation: College of Pharmacy, Chungnam National University, 99 Daehak-ro, Yuseong-gu, Daejeon 34134, South Korea. Electronic address: shwoo@cnu.ac.kr.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Woo
mesh_terms: D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D020746:Calcium Channels, L-Type / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002227:Carbazoles / Q000494:pharmacology*; D055724:Electrophysiological Phenomena / Q000187:drug effects*; D006352:Heart Ventricles / Q000166:cytology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000470:Alkaloids; D020746:Calcium Channels, L-Type; D002227:Carbazoles; C443728:murrayafoline A; D011493:Protein Kinase C; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2
keywords: L-type Ca(2+) current; Murrayafoline-A; Murrayafoline-A (PubChem CID: 375150); PKC; Positive inotropy; Ventricular myocytes