Inner sarcolemmal leaflet Ca$^2+$ binding: its role in cardiac
Na/Ca exchange.
Biophys. J., 70 (5):
2266--2274 (May 1996)Abstract
A recently completed model of Ca concentration and movements in the
cardiac cell diadic cleft space predicts that removal or neutralization
of inner sarcolemmal (SL) leaflet anionic Ca-binding sites at the
sarcolemmal border of this space will greatly diminish Na/Ca exchange-mediated
Ca efflux. The present study tests this prediction using the local
anesthetic dibucaine as a probe. It is shown, in isolated SL, that
dibucaine competitively displaces Ca specifically from anionic phospholipid
headgroups. Dibucaine also displaces Ca from the SL when applied
to intact cells. It does not affect the content or release of Ca
from sarcoplasmic reticulum (SR) in these cells. This eliminates
a primary effect on SR Ca as a contributing factor to dibucaine's
effect on Na/Ca exchange-mediated Ca efflux. Measurement of this
efflux from whole cells shows a highly significant reduction of 58\%
(p < 0.001) by 0.5 mM dibucaine. The inhibiting effect of dibucaine
on Na/Ca exchange-mediated Ca efflux can be significantly reversed
by augmentation of Ca release from SR by caffeine at the time of
activation of Na/Ca exchange. This supports the contention that the
dibucaine-SL interaction is a competitive one vis-a-vis Ca. The
results are supportive of the model in which inner SL leaflet Ca-binding
sites account for the delay of Ca diffusion from the diadic cleft,
thereby prolonging the time for which Ca remains elevated in the
cleft. The prolonged increased Ca significantly enhances the ability
of Na/Ca exchange to remove Ca from the cell during the excitation-contraction
cycle.
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