Seidler, T., Loughrey, C., Zibrova, D., Kettlewell, S., Teucher, N., Kogler, H., Hasenfuss, G. and Smith, G. (2007) Overexpression of FK-506-binding protein 12.0 modulates excitation-contraction coupling in adult rabbit ventricular cardiomyocytes. Circulation Research, 101(10), pp. 1020-1029. (doi: 10.1161/CIRCRESAHA.107.154609)
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Abstract
The effect of the 12-kDa isoform of FK-506-binding protein (FKBP)12.0 on cardiac excitation contraction coupling was studied in adult rabbit ventricular myocytes after transfection with a recombinant adenovirus coding for human FKBP12.0 (Ad-FKBP12.0). Western blots confirmed overexpression (by 2.6 +/- 0.4 fold, n = 5). FKBP12.0 association with rabbit cardiac ryanodine receptor (RyR2) was not detected by immunoprecipitation. However, glutathione S-transferase pull-down experiments indicated FKBP12.0-RyR2 binding to proteins isolated from human and rabbit but not dog myocardium. Voltage-clamp experiments indicated no effects of FKBP12.0 overexpression on L-type Ca2+ current (I-Ca,I-L) or Ca2+ efflux rates via the Na+/Ca2+ exchanger. Ca2+ transient amplitude was also not significantly different. However, sarcoplasmic reticulum Ca2+ load was approximate to 25% higher in myocytes in the Ad-FKBP12.0 group. The reduced ability of ICa, L to initiate sarcoplasmic reticulum Ca2+ release was observed over a range of values of sarcoplasmic reticulum Ca2+ content, indicating that overexpression of FKBP12.0 reduces the sensitivity of RyR2 to Ca2+. Ca2+ spark morphology was measured in beta-escin-permeabilized cardiomyocytes. Ca2+ spark amplitude and duration were significantly increased, whereas frequency was decreased in cells overexpressing FKBP12.0. These changes were accompanied by an increased sarcoplasmic reticulum Ca2+ content. In summary, the effects of FKBP12.0 overexpression on intact and permeabilized cells were similar to those of tetracaine, a drug known to reduce RyR2 Ca2+ sensitivity and distinctly different from the effects of overexpression of the FKBP12.6 isomer. In conclusion, FKBP12.0-RyR2 interaction can regulate the gain of excitation-contraction coupling.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Smith, Professor Godfrey and Kettlewell, Dr Sarah and Loughrey, Professor Christopher |
| Authors: | Seidler, T., Loughrey, C., Zibrova, D., Kettlewell, S., Teucher, N., Kogler, H., Hasenfuss, G., and Smith, G. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health College of Medical Veterinary and Life Sciences |
| Journal Name: | Circulation Research |
| ISSN: | 0009-7330 |
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