Premium
Equilibrium between adenylyl cyclase and phosphodiesterase patterns adrenergic agonist dose‐dependent spatiotemporal cAMP/PKA activities
Author(s) -
Xiang Yang K
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1012.3
Subject(s) - adenylyl cyclase , agonist , phosphodiesterase , chemistry , medicine , protein kinase a , endocrinology , phospholamban , intrinsic activity , pde10a , phosphorylation , gs alpha subunit , forskolin , receptor , adrenergic receptor , biophysics , biology , enzyme , biochemistry
Beta‐adrenergic receptor induces cAMP/Protein kinase A (PKA) activation to regulate cardiac contraction. Using real‐time detection of cAMP and PKA activities, we show two distinct phases in isoproterenol dose‐dependent responses: a transient and dose‐dependent increase in cAMP and PKA activities at concentrations from 10–12 to 10‐8 M; and a saturated initial increases at concentrations from 10‐8 to 10‐5 M followed by a rapid decrease to different levels that were later sustained in a dose‐dependent manner. The dose‐dependent temporal responses are patterned by equilibrium between receptor‐activated adenylyl cyclase (AC) and phosphodiesterase (PDE). At lower concentrations, cAMP is produced in an agonist dose‐dependent manner with AC as a rate‐limiting factor. However, the cAMP activities are confined within local domains for phosphorylation of local substrates. At higher concentrations, isoproterenol promotes a dose‐dependent selective dissociation of PDE4D but not ACVI from the receptor complex, which shifts the equilibrium between AC and PDE. This shifted balance leads to sustained cAMP accumulation and diffusion for PKA phosphorylation of phospholamban and troponin I, and for myocyte contraction. Our data reveal a new paradigm for adrenergic agonist dose‐dependent cAMP/PKA activities for substrate‐specific phosphorylation dictated by dual regulation of AC and PDE in cardiomyocytes.