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Departments of Pharmacology and Medicine, Medical College of Ohio, Toledo, Ohio 43614
Ouabain binding to
Na+/K+-ATPase activates Src/epidermal growth
factor receptor (EGFR) to initiate multiple signal pathways that
regulate growth. In cardiac myocytes and the intact heart, the early
ouabain-induced pathways that cause rapid activations of ERK1/2 also
regulate intracellular Ca2+ concentration
([Ca2+]i) and contractility. The goal of this
study was to explore the role of caveolae in these early signaling
events. Subunits of Na+/K+-ATPase were detected
by immunoblot analysis in caveolae isolated from cardiac myocytes,
cardiac ventricles, kidney cell lines, and kidney outer medulla by
established detergent-free procedures. Isolated rat cardiac caveolae
contained Src, EGFR, ERK1/2, and 20-30% of cellular contents of
1- and 2-isoforms of
Na+/K+-ATPase, along with nearly all of
cellular caveolin-3. Immunofluorescence microscopy of adult cardiac
myocytes showed the presence of caveolin-3 and -isoforms in
peripheral sarcolemma and T tubules and suggested their partial
colocalization. Exposure of contracting isolated rat hearts to a
positive inotropic dose of ouabain and analysis of isolated cardiac
caveolae showed that ouabain caused 1) no change in total
caveolar ERK1/2, but a two- to threefold increase in caveolar
phosphorylated/activated ERK1/2; 2) no change in caveolar 1-isoform and caveolin-3; and 3) 50-60%
increases in caveolar Src and 2-isoform. These findings,
in conjunction with previous observations, show that components of the
pathways that link Na+/K+-ATPase to ERK1/2 and
[Ca2+]i are organized within cardiac caveolae
microdomains. They also suggest that ouabain-induced recruitments of
Src and 2-isoform to caveolae are involved in the
manifestation of the positive inotropic effect of ouabain.
digitalis; heart failure; rafts; sodium pump; Na+/Ca2+ exchanger
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