| Autor: |
McDowell, Susan A., McCall, Eileen, Matter, William F., Estridge, Thomas B., Vlahos, Chris J. |
| Předmět: |
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| Zdroj: |
American Journal of Physiology: Heart & Circulatory Physiology; Feb2004, Vol. 286 Issue 2, pH796-H805, 10p, 1 Black and White Photograph, 33 Graphs |
| Abstrakt: |
Phosphoinositide 3-kinase regulates excitation-contraction coupling in neonatal cardiomyocytes. Am J Physiol Heart Circ Physio1286: H796–H805, 2004. First published October 16, 2003; 10.1152/ajpheart.00546.2003.—The phosphoinositide 3-kinase (PI3K) inhibitor LY-294002 decreased steady-state contraction in neonatal rat ventricular myocytes (NRVM). To determine whether the effect on steady-state contraction could be due to decreased intracellular Ca²+ content, Ca²+ content was assessed with fluorescent plate reader analysis by using the caffeine-releasable Ca²+ stores as an index of sarcoplasmic reticulum (SR) Ca²+ content. Caffeine-releasable Ca²+ content was diminished in a dose-dependent manner with LY-294002, suggesting that the decrease in steady-state contraction was due to diminished intracellular Ca²+ content. Activation of the L-type Ca²+ channel by BAY K 8644 was attenuated by LY-294002, suggesting the effect of LY294002 is to reduce Ca²+ influx at this channel. To investigate whether additional proteins involved in excitation-contraction (EC) coupling are likewise regulated by PI3K activity, the effects of compounds acting at sarco(endo)plasmic reticulum Ca²+-ATPase (SERCA2a), the ryanodine receptor, and the Na/Ca exchanger (NCX) were compared with LY-294002. Inhibition of SERCA2a by thapsigargin increased basal Ca²+ levels in contrast to LY-294002, indicating that SERCA2a activity is sustained in the presence of LY-294002. Ryanodine decreased SR Ca²+ content. The additive effect with coadministration of LY-294002 could be attributed to a decrease in Ca²+ influx at the L-type Ca²+ channel. The NCX inhibitor Ni²+ was used to investigate whether the decrease in intracellular Ca²+ content with LY-294002 could be due to inhibition of the NCX reverse-mode activity. The minimal effect of LY-294002 with Ni²+ suggests that the primary effect of LY-294002 on EC coupling occurs through inhibition of PI3K-mediated L-type Ca²+ channel activity. [ABSTRACT FROM AUTHOR] |
| Databáze: |
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