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Am J Physiol Heart Circ Physiol (October 16, 2003). doi:10.1152/ajpheart.00546.2003
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Submitted on June 12, 2003
Accepted on October 7, 2003

Phosphoinositide 3-kinase (PI3K) regulates excitation-contraction coupling in neonatal cardiomyocytes

Susan A McDowell1, Eileen McCall1, William F Matter1, Thomas B Estridge1, and Chris J Vlahos1*

1 Cardiovascular Research, Eli Lilly and Company, Indianapolis, IN, USA

* To whom correspondence should be addressed. E-mail: vlahos_chris_j{at}lilly.com.

The phosphoinositide 3-kinase (PI3K) inhibitor LY294002 decreased steady-statecontraction 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 (FLIPR) analysis, 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 LY294002, suggesting that the decrease in steadystate contraction was due to diminished intracellular Ca2+ content. Activation of the L-type Ca2+ channel by BAY K 8644 was attenuated by LY294002, 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 SERCA-2a, the ryanodine receptor, and the Na-Ca exchanger (NCX), were compared to LY294002. Inhibition of SERCA-2a by thapsigargin increased basal Ca2+ levels in contrast to LY294002, indicating that SERCA-2a activity is sustained in the presence of LY294002. Ryanodine decreased SR Ca2+ content. The additive effect with co-administration of LY294002 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 LY294002 could be due to inhibition of NCX reverse mode activity. The minimal effect of LY294002 with Ni2+ suggests that the primary effect of LY294002 on EC-coupling occurs through inhibition of PI3K mediated L-type Ca2+ channel activity.




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