TY - JOUR
T1 - Functional roles of KATP channel subunits in metabolic inhibition
AU - Glukhov, Alexey V.
AU - Uchida, Keita
AU - Efimov, Igor R.
AU - Nichols, Colin G.
N1 - Funding Information:
This work was supported by NIH grant HL95010 to CGN. We are grateful to Matt Sulkin for technical assistance and for providing an updated version of the Matlab based analysis GUI. We also thank Haixia Zhang for her helpful discussion and for critically reviewing the data and manuscript. Finally, we thank Drs. Susumu Seino for the Kir6.2 −/− mice and Mark Magnuson for the SUR1 −/− mice.
PY - 2013/9
Y1 - 2013/9
N2 - ATP-sensitive potassium channel (KATP) activation can drastically shorten action potential duration (APD) in metabolically compromised myocytes. We showed previously that SUR1 with Kir6.2 forms the functional channel in mouse atria while Kir6.2 and SUR2A predominate in ventricles. SUR1 is more sensitive to metabolic stress than SUR2A, raising the possibility that KATP in atria and ventricles may respond differently to metabolic stress. Action potential duration (APD) and calcium transient duration (CaTD) were measured simultaneously in both atria and ventricles by optical mapping of the posterior surface of Langendorff-perfused hearts from C57BL wild-type (WT; n=11), Kir6.2-/- (n=5), and SUR1-/- (n=6) mice during metabolic inhibition (MI, 0mM glucose+2mM sodium cyanide). After variable delay, MI led to significant shortening of APD in WT hearts. On average, atrial APD shortened by 60.5±2.7% at 13.1±2.1min (n=6, p<0.01) after onset of MI. Ventricular APD shortening (56.4±10.0% shortening at 18.2±1.8min) followed atrial APD shortening. In SUR1-/- hearts (n=6), atrial APD shortening was abolished, but ventricular shortening (65.0±15.4% at 25.33±4.48min, p<0.01) was unaffected. In Kir6.2-/- hearts, two disparate responses to MI were observed; 3 of 5 hearts displayed slight shortening of APD in the ventricles (24±3%, p<0.05) and atria (39.0±1.9%, p<0.05) but this shortening occurred later and to much less extent than in WT (p<0.05). Marked prolongation of ventricular APD was observed in the remaining hearts (327% and 489% prolongation) and was associated with occurrence of ventricular tachyarrhythmias. The results confirm that Kir6.2 contributes to APD shortening in both atria and ventricle during metabolic stress, and that SUR1 is required for atrial APD shortening while SUR2A is required for ventricular APD shortening. Importantly, the results show that the presence of SUR1-dependent KATP in the atria results in the action potential being more susceptible to metabolically driven shortening than the ventricle.
AB - ATP-sensitive potassium channel (KATP) activation can drastically shorten action potential duration (APD) in metabolically compromised myocytes. We showed previously that SUR1 with Kir6.2 forms the functional channel in mouse atria while Kir6.2 and SUR2A predominate in ventricles. SUR1 is more sensitive to metabolic stress than SUR2A, raising the possibility that KATP in atria and ventricles may respond differently to metabolic stress. Action potential duration (APD) and calcium transient duration (CaTD) were measured simultaneously in both atria and ventricles by optical mapping of the posterior surface of Langendorff-perfused hearts from C57BL wild-type (WT; n=11), Kir6.2-/- (n=5), and SUR1-/- (n=6) mice during metabolic inhibition (MI, 0mM glucose+2mM sodium cyanide). After variable delay, MI led to significant shortening of APD in WT hearts. On average, atrial APD shortened by 60.5±2.7% at 13.1±2.1min (n=6, p<0.01) after onset of MI. Ventricular APD shortening (56.4±10.0% shortening at 18.2±1.8min) followed atrial APD shortening. In SUR1-/- hearts (n=6), atrial APD shortening was abolished, but ventricular shortening (65.0±15.4% at 25.33±4.48min, p<0.01) was unaffected. In Kir6.2-/- hearts, two disparate responses to MI were observed; 3 of 5 hearts displayed slight shortening of APD in the ventricles (24±3%, p<0.05) and atria (39.0±1.9%, p<0.05) but this shortening occurred later and to much less extent than in WT (p<0.05). Marked prolongation of ventricular APD was observed in the remaining hearts (327% and 489% prolongation) and was associated with occurrence of ventricular tachyarrhythmias. The results confirm that Kir6.2 contributes to APD shortening in both atria and ventricle during metabolic stress, and that SUR1 is required for atrial APD shortening while SUR2A is required for ventricular APD shortening. Importantly, the results show that the presence of SUR1-dependent KATP in the atria results in the action potential being more susceptible to metabolically driven shortening than the ventricle.
UR - http://www.scopus.com/inward/record.url?scp=84880959444&partnerID=8YFLogxK
U2 - 10.1016/j.yjmcc.2013.04.016
DO - 10.1016/j.yjmcc.2013.04.016
M3 - Article
C2 - 23624089
AN - SCOPUS:84880959444
SN - 0022-2828
VL - 62
SP - 90
EP - 98
JO - Journal of Molecular and Cellular Cardiology
JF - Journal of Molecular and Cellular Cardiology
ER -