Kang, YH and Ng, B and Leung, YM and He, Y and Xie, HL and Lodwick, D and Norman, RI and Tinker, A and Tsushima, RG and Gaisano, HY (2006) Syntaxin-1A actions on sulfonylurea receptor 2A can block acidic pH-induced cardiac K-ATP channel activation. J BIOL CHEM , 281 (28) 19019 - 19028. 10.1074/jbc.M513160200.
During cardiac ischemia, ATP stores are depleted, and cardiomyocyte intracellular pH lowers to < 7.0. The acidic pH acts on the Kir6.2 subunit of K-ATP channels to reduce its sensitivity to ATP, causing channel opening. We recently reported that syntaxin-1A (Syn-1A) binds nucleotide binding folds (NBF)-1 and NBF2 of sulfonylurea receptor 2A (SUR2A) to inhibit channel activity (Kang, Y., Leung, Y. M., Manning-Fox, J. E., Xia, F., Xie, H., Sheu, L., Tsushima, R. G., Light, P. E., and Gaisano, H. Y. (2004) J. Biol. Chem. 279, 47125-47131). Here, we examined Syn-1A actions on SUR2A to influence the pH regulation of cardiac K-ATP channels. K-ATP channel currents from inside-out patches excised from Kir6.2/SUR2A expressing HEK293 cells and freshly isolated cardiac myocytes were increased by reducing intracellular pH from 7.4 to 6.8, which could be blocked by increasing concentrations of Syn-1A added to the cytoplasmic surface. Syn-1A had no effect on C-terminal truncated Kir6.2 (Kir6.2-Delta C26) channels expressed in TSA cells without the SUR subunit. In vitro binding and co-immunoprecipitation studies show that Syn-1A binding to SUR2A or its NBF-1 and NBF-2 domain proteins increased progressively as pH was reduced from 7.4 to 6.0. The enhancement of Syn-1A binding to SUR2A by acidic pH was further regulated by Mg2+ and ATP. Therefore, pH regulates Kir.6.2/SUR2A channels not only by its direct actions on the Kir6.2 subunit but also by modulation of Syn-1A binding to SUR2A. The increased Syn-1A binding to the SUR2A at acidic pH would assert some inhibition of the K-ATP channels, which may serve as a "brake" to temper the fluctuation of low pH-induced K-ATP channel opening that could induce fatal re-entrant arrhythmias.
|Title:||Syntaxin-1A actions on sulfonylurea receptor 2A can block acidic pH-induced cardiac K-ATP channel activation|
|Open access status:||An open access publication|
|Keywords:||SENSITIVE POTASSIUM CHANNELS, NUCLEAR MAGNETIC-RESONANCE, ISCHEMIC RAT-HEART, SKELETAL-MUSCLE, VENTRICULAR MYOCARDIUM, INTRACELLULAR H+, REPERFUSION, INHIBITION, MODULATION, MAGNESIUM|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
Archive Staff Only: edit this record