磺酰脲类受体2型依赖的KATP通道在缺血预适应中的调控作用-英文.ppt
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1、Regulation and Roles of the Sulfonylurea Receptor 2-Based KATP Channels in Ischemic Preconditioning,Bin Ye1, Jie-lin Pu1, Tomoyki Wada1, Jason Sims2, Stacie Kroboth1, Douglas Stoller1, Elizabeth McNally3, Jonathan Makielski1, Nian-Qing Shi1* nqsmedicine.wisc.edu 1Department of Medicine, University o
2、f Wisconsin, Madison, WI USA 2Department of Pharmacology, University of Wisconsin, Madison, WI USA 3Department of Medicine, The University of Chicago, Chicago, IL USA,The Cellular and Molecular Arrhythmia Research Program,Ion Channels Play Pivotal Roles in Cardiac Functions and Protection, Situate o
3、n plasma membrane Contain multiple transmembrane helixes Opening of ion channels is within milliseconds Impact the electrophysiological state of the cell Mutations in ion channels are linked to many cardiovascular diseases (i.e. Long QT syndrome), Noma (1983): Sarcolemmal KATP, Inoue et al. (1991):
4、Mitochondrial KATP,K+,Mitochondrion,KATP channels open in ischemia like metabolic sensors of the cell,Cardiac ATP-sensitive Potassium Channels (KATP),Reviewed by Shi, Ye, Makielski (2005) JMCC 39:51,N,1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17,C,Sulfonylurea Receptor (ATP-binding cassette protein),SU
5、R2A (Major cardiac splice variant) SUR2B (Major smooth muscle splice variant),175 kDa,RKR,M1 M2,P loop,N,C,RKR,Pore (K+ inward rectifier),Kir6.2,48 kDa,Structure of Cardiac KATP Channels,TMD0 TMD1 TMD2,Ischemia is a disease condition where the heart has insufficient levels of oxygen and blood supply
6、 Acute myocardial infarction is a life-threatening event that can cause sudden death and heart failure Blocking KATP channels during ischemia abolishes cardioprotection (Gross & Auchampach, 1992) The opening of KATP can re-polarize the cell membrane, reduce calcium entry and decrease ATP consumption
7、 MitoKATP is more likely to confer cardioprotection (Garlid et al., 1996 & 1997) but its molecular nature is not completely understood,Ischemia and KATP Channels,Reviewed by Gross et al., 2003,IPC is a natural phenomenon where brief periods of ischemia provide in vivo protection from subsequent leth
8、al ischemia that can cause infarction Acute IPC: where the protective period lasts for few hours after the preconditioning stimulus Delayed IPC (SWOP): where the protective period can last for 24-72 h after the preconditioning stimulus,Ischemic Preconditioning (IPC),Reviewed by Yellon & Downey, 2003
9、,Stimulus-Memory-Protection,Hypothesis: Losing the regulatory subunit of cardiac KATP leads to reduced cardiac protection,Chutkow, Pu, Wada, Makielski, Burant, McNally. PNAS (2001) 98:11760 Kakkar, Ye, Shi, Makielski, McNally et al., Cir Res (2006) 98:675,SUR2 Knockout Mutant Mice,Exon12-16,Glibencl
10、amide (a KATP blocker) action sites,The Glibenclamide-Sensitive KATP Current is Absent in the Mutant Myocytes and VSM Cells,WT,Mutant,Chutkow et al (2001) PNAS 98:11760,A Glibenclamide-Insensitive KATP Current (IKATPn) is recorded in KO mice,Pu*, Ye*, McNally, Makielski, Shi (2008) JMCC 44:188,IKATP
11、n is More Sensitive to ATP,Kinetics of IKATPn Differ from the Conventional IKATP,Mean burst duration (ms),WT SUR2 Mutant,44.29.5,20.61.8,WT SUR2 Mutant,pS,WT SUR2 Mutant,PO,23.71.1,23.11.2,0.540.13,0.490.12,Duration Time (ms),Total number of bursts,WT,SUR2 Mutant,IKATPn is Glibenclamide-Insensitive,
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