PDE4B mediates local feedback regulation of ß1-adrenergic cAMP signaling in a sarcolemmal compartment of cardiac myocytes.
J Cell Sci
; 127(Pt 5): 1033-42, 2014 Mar 01.
Article
in En
| MEDLINE
| ID: mdl-24413164
ABSTRACT
Multiple cAMP phosphodiesterase (PDE) isoforms play divergent roles in cardiac homeostasis but the molecular basis for their non-redundant function remains poorly understood. Here, we report a novel role for the PDE4B isoform in ß-adrenergic (ßAR) signaling in the heart. Genetic ablation of PDE4B disrupted ßAR-induced cAMP transients, as measured by FRET sensors, at the sarcolemma but not in the bulk cytosol of cardiomyocytes. This effect was further restricted to a subsarcolemmal compartment because PDE4B regulates ß1AR-, but not ß2AR- or PGE2-induced responses. The spatially restricted function of PDE4B was confirmed by its selective effects on PKA-mediated phosphorylation patterns. PDE4B limited the PKA-mediated phosphorylation of key players in excitation-contraction coupling that reside in the sarcolemmal compartment, including L-type Ca(2+) channels and ryanodine receptors, but not phosphorylation of distal cytosolic proteins. ß1AR- but not ß2AR-ligation induced PKA-dependent activation of PDE4B and interruption of this negative feedback with PKA inhibitors increased sarcolemmal cAMP. Thus, PDE4B mediates a crucial PKA-dependent feedback that controls ß1AR-dependent cAMP signals in a restricted subsarcolemmal domain. Disruption of this feedback augments local cAMP/PKA signals, leading to an increased intracellular Ca(2+) level and contraction rate.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Sarcolemma
/
Receptors, Adrenergic, beta-1
/
Cyclic AMP
/
Myocytes, Cardiac
/
Cyclic Nucleotide Phosphodiesterases, Type 4
Limits:
Animals
Language:
En
Journal:
J Cell Sci
Year:
2014
Type:
Article
Affiliation country:
United States