title: Compartmentalization of beta-adrenergic signals in cardiomyocytes.
abstract: Activation of adrenergic receptors (AR) represents the primary mechanism to increase cardiac performance under stress. Activated βAR couple to Gs protein, leading to adenylyl cyclase-dependent increases in secondary-messenger cyclic adenosine monophosphate (cAMP) to activate protein kinase A. The increased protein kinase A activities promote phosphorylation of diversified substrates, ranging from the receptor and its associated partners to proteins involved in increases in contractility and heart rate. Recent progress with live-cell imaging has drastically advanced our understanding of the βAR-induced cAMP and protein kinase A activities that are precisely regulated in a spatiotemporal fashion in highly differentiated myocytes. Several features stand out: membrane location of βAR and its associated complexes dictates the cellular compartmentalization of signaling; βAR agonist dose-dependent equilibrium between cAMP production and cAMP degradation shapes persistent increases in cAMP signals for sustained cardiac contraction response; and arrestin acts as an agonist dose-dependent master switch to promote cAMP diffusion and propagation into intracellular compartments by sequestrating phosphodiesterase isoforms associated with the βAR signaling cascades. These features and the underlying molecular mechanisms of dynamic regulation of βAR complexes with adenylyl cyclase and phosphodiesterase enzymes and the implication in heart failure are discussed.
authors: Molecular and Integrative Physiology, University of Illinois at Urbana Champaign, Urbana, IL, USA. kevinyx@illinois.edu
authors: Yang K
authors: YK
authors: Xiang
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D006801:Humans; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D011943:Receptors, Adrenergic, beta; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases