The Na$^+$-Ca$^2+$ exchanger (NCX) is one of the essential
regulators of Ca$^2+$ homeostasis in cardiomyocytes and thus
an important modulator of the cardiac contractile function. The purpose
of this review is to survey recent advances in cardiac NCX research,
with particular emphasis on molecular and pharmacological aspects.
The NCX function is thought to be regulated by a variety of cellular
factors. However, data obtained by use of different experimental
systems often appear to be in conflict. Where possible, we endeavor
to provide a rational interpretation of such data. We also provide
a summary of current work relating to the structure and function
of the cardiac NCX. Recent molecular studies of the NCX protein are
beginning to shed light on structural features of the ion translocation
pathway in the NCX membrane domain, which seems likely to be formed,
at least partly, by the phylogenetically conserved alpha-1 and alpha-2
repeat structures and their neighboring membrane-spanning segments.
Finally, we discuss new classes of NCX inhibitors with improved selectivity.
One of these, 2-2-4-(4-nitrobenzyloxy)phenylethylisothiourea
methanesulfonate (KB-R7943), appears to exhibit unique selectivity
for Ca$^2+$-influx-mode NCX activity. Data obtained with these
inhibitors should provide a basis for designing more selective and
clinically useful drugs targeting NCX.