Abstract
The beta1- and beta2-adrenergic receptors (betaARs) on the surface
of cardiomyocytes mediate distinct effects on cardiac function and
the development of heart failure by regulating production of the
second messenger cyclic adenosine monophosphate (cAMP). The spatial
localization in cardiomyocytes of these betaARs, which are coupled
to heterotrimeric guanine nucleotide-binding proteins (G proteins),
and the functional implications of their localization have been unclear.
We combined nanoscale live-cell scanning ion conductance and fluorescence
resonance energy transfer microscopy techniques and found that, in
cardiomyocytes from healthy adult rats and mice, spatially confined
beta2AR-induced cAMP signals are localized exclusively to the deep
transverse tubules, whereas functional beta1ARs are distributed across
the entire cell surface. In cardiomyocytes derived from a rat model
of chronic heart failure, beta2ARs were redistributed from the transverse
tubules to the cell crest, which led to diffuse receptor-mediated
cAMP signaling. Thus, the redistribution of beta(2)ARs in heart failure
changes compartmentation of cAMP and might contribute to the failing
myocardial phenotype.
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