title: ATP-sensitive potassium currents from channels formed by Kir6 and a modified cardiac mitochondrial SUR2 variant.
abstract: Cardiac ATP-sensitive potassium channels (KATP) are found in both the sarcoplasmic reticulum (sarcKATP) and the inner membrane of mitochondria (mitoKATP). SarcKATP are composed of a pore containing subunit Kir6.2 and a regulatory sulfonylurea receptor subunit (SUR2), but the composition of mitoKATP remains unclear. An unusual intra-exonic splice variant of SUR2 (SUR2A-55) was previously identified in mitochondria of mammalian heart and brain, and by analogy with sarcKATP we proposed SUR2A-55 as a candidate regulatory subunit of mitoKATP. Although SUR2A-55 lacks the first nucleotide binding domain (NBD) and 2 transmembrane domains (TMD), it has a hybrid TMD and retains the second NBD. It resembles a hemi-ABC transporter suggesting it could multimerize to function as a regulatory subunit. A putative mitochondrial targeting signal in the N-terminal domain of SUR2A-55 was removed by truncation and when co-expressed with Kir6.1 and Kir6.2 it targeted to the plasma membrane and yielded KATP currents. Single channel conductance, mean open time, and burst open time of SUR2A-55 based KATP was similar to the full-length SUR2A based KATP. However, the SUR2A-55 KATP were 70-fold less sensitive to block by ATP, and twice as resistant to intracellular Ca (2+) inhibition compared with the SUR2A KATP, and were markedly insensitive to KATP drugs, pinacidil, diazoxide, and glybenclamide. These results suggest that the SUR2A-55 based channels would tend to be open under physiological conditions and in ischemia, and could account for cardiac and mitochondrial phenotypes protective for ischemia.
authors.affiliation: Department of Medicine; University of Wisconsin; Madison, WI USA.
authors.forename: Nitin T
authors.initials: NT
authors.lastname: Aggarwal
authors.affiliation: Department of Medicine; University of Wisconsin; Madison, WI USA.
authors.forename: Nian-Qing
authors.initials: NQ
authors.lastname: Shi
authors.affiliation: Department of Medicine; University of Wisconsin; Madison, WI USA.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Makielski
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D055724:Electrophysiological Phenomena; D054086:KATP Channels / Q000378:metabolism*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D009206:Myocardium / Q000166:cytology*; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism*; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D064233:Sulfonylurea Receptors / Q000378:metabolism*; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D002118:Calcium; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D020033:Protein Isoforms; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577511:Abcc9 protein, mouse; C092520:uK-ATP-1 potassium channel
keywords: ATP-binding cassette protein; KATP channel; alternative splicing; hemi-transporter; intra-exonic splice variant; inward rectifier channel; ischemic preconditioning; mitochondria; sulfonylurea receptor
references.citation: J Biol Chem. 1996 Apr 12;271(15):8796-9
references.pmid: 8621517
references.citation: J Biol Chem. 1996 Oct 4;271(40):24321-4
references.pmid: 8798681
references.citation: Circ Res. 1997 Dec;81(6):1072-82
references.pmid: 9400389
references.citation: Circ Res. 2012 Aug 3;111(4):446-54
references.pmid: 22811560
references.citation: Int J Biochem Cell Biol. 2013 Feb;45(2):283-91
references.pmid: 23085378
references.citation: Proc Natl Acad Sci U S A. 2001 Sep 25;98(20):11760-4
references.pmid: 11562480
references.citation: Nature. 1983 Sep 8-14;305(5930):147-8
references.pmid: 6310409
references.citation: J Biol Chem. 2004 Oct 8;279(41):42954-63
references.pmid: 15215243
references.citation: J Biol Chem. 1983 Nov 25;258(22):13411-4
references.pmid: 6417126
references.citation: Physiol Rev. 2010 Jul;90(3):799-829
references.pmid: 20664073
references.citation: J Physiol. 1998 Jul 15;510 ( Pt 2):333-45
references.pmid: 9705987
references.citation: J Gen Physiol. 1999 Aug;114(2):251-69
references.pmid: 10436001
references.citation: J Mol Cell Cardiol. 2008 Jan;44(1):188-200
references.pmid: 18001767
references.citation: J Biol Chem. 2003 Oct 24;278(43):41577-80
references.pmid: 12941953
references.citation: Circ Res. 2009 Nov 20;105(11):1083-93
references.pmid: 19797704
references.citation: J Biol Chem. 1999 Oct 1;274(40):28079-82
references.pmid: 10497157
references.citation: Biochim Biophys Acta. 1988 Aug 18;943(2):297-304
references.pmid: 2456785
references.citation: J Mol Cell Cardiol. 2005 Jul;39(1):51-60
references.pmid: 15978902
references.citation: Genome Res. 2001 Jul;11(7):1156-66
references.pmid: 11435397
references.citation: Circulation. 1986 Nov;74(5):1124-36
references.pmid: 3769170
references.citation: Physiol Rev. 1998 Jan;78(1):227-45
references.pmid: 9457174
references.citation: Diabetes. 1996 Oct;45(10):1439-45
references.pmid: 8826984
references.citation: EMBO J. 2000 Dec 15;19(24):6644-51
references.pmid: 11118199
references.citation: Am J Physiol Heart Circ Physiol. 2010 Dec;299(6):H1884-90
references.pmid: 20935152
references.citation: Biochem Biophys Res Commun. 2008 Feb 15;366(3):649-56
references.pmid: 18068667
references.citation: J Biol Chem. 2000 Jan 14;275(2):717-20
references.pmid: 10625598
references.citation: Nature. 1991 Jul 18;352(6332):244-7
references.pmid: 1857420
references.citation: J Physiol. 1993 Jun;465:163-79
references.pmid: 8229832
references.citation: EMBO J. 2003 Aug 1;22(15):3833-43
references.pmid: 12881418
references.citation: Biochim Biophys Acta. 2004 May 12;1656(1):46-56
references.pmid: 15136158
references.citation: Adv Exp Med Biol. 1986;194:573-90
references.pmid: 3092593
references.citation: Neuron. 1996 May;16(5):1011-7
references.pmid: 8630239
references.citation: J Mol Cell Cardiol. 2007 Oct;43(4):445-54
references.pmid: 17765261
references.citation: Circ Res. 1993 Mar;72(3):715-22
references.pmid: 8381726
references.citation: Circ Res. 2006 Mar 17;98(5):682-9
references.pmid: 16456098
references.citation: Circ Res. 1992 Feb;70(2):223-33
references.pmid: 1310443
references.citation: Physiol Rev. 2003 Oct;83(4):1113-51
references.pmid: 14506302
references.citation: Nature. 1997 May 8;387(6629):179-83
references.pmid: 9144288