Zusammenfassung
Many different receptors can stimulate cAMP synthesis in the heart,
but not all elicit the same functional responses. For example, it
has been recognized for some time that prostaglandins such as PGE1
increase cAMP production and activate PKA, but they do not elicit
responses like those produced by beta-adrenergic receptor (betaAR)
agonists such as isoproterenol (isoprenaline), even though both stimulate
the same signalling pathway. In the present study, we confirm that
isoproterenol, but not PGE1, is able to produce cAMP-dependent stimulation
of the L-type Ca(2+) current in guinea pig ventricular myocytes.
This is despite finding evidence that these cells express EP(4) prostaglandin
receptors, which are known to activate G(s)-dependent signalling
pathways. Using fluorescence resonance energy transfer-based biosensors
that are either freely diffusible or bound to A kinase anchoring
proteins, we demonstrate that the difference is due to the ability
of isoproterenol to stimulate cAMP production in cytosolic and caveolar
compartments of intact cardiac myocytes, while PGE1 only stimulates
cAMP production in the cytosolic compartment. Unlike other receptor-mediated
responses, compartmentation of PGE1 responses was not due to concurrent
activation of a G(i)-dependent signalling pathway or phosphodiesterase
activity. Instead, compartmentation of the PGE1 response in cardiac
myocytes appears to be due to transient stimulation of cAMP in a
microdomain that can communicate directly with the bulk cytosolic
compartment but not the caveolar compartment associated with betaAR
regulation of L-type Ca(2+) channel function.
Nutzer