title: Adenylyl cyclase subtype-specific compartmentalization: differential regulation of L-type Ca2+ current in ventricular myocytes.
abstract: BACKGROUND
  Adenylyl cyclase (AC) represents one of the principal molecules in the β-adrenergic receptor signaling pathway, responsible for the conversion of ATP to the second messenger, cAMP. AC types 5 (ACV) and 6 (ACVI) are the 2 main isoforms in the heart. Although highly homologous in sequence, these 2 proteins play different roles during the development of heart failure. Caveolin-3 is a scaffolding protein, integrating many intracellular signaling molecules in specialized areas called caveolae. In cardiomyocytes, caveolin is located predominantly along invaginations of the cell membrane known as t-tubules.
  
  
  OBJECTIVE
  We take advantage of ACV and ACVI knockout mouse models to test the hypothesis that there is distinct compartmentalization of these isoforms in ventricular myocytes.
  
  
  RESULTS
  We demonstrate that ACV and ACVI isoforms exhibit distinct subcellular localization. The ACVI isoform is localized in the plasma membrane outside the t-tubular region and is responsible for β1-adrenergic receptor signaling-mediated enhancement of the L-type Ca(2+) current (ICa,L) in ventricular myocytes. In contrast, the ACV isoform is localized mainly in the t-tubular region where its influence on ICa,L is restricted by phosphodiesterase. We further demonstrate that the interaction between caveolin-3 with ACV and phosphodiesterase is responsible for the compartmentalization of ACV signaling.
  
  
  CONCLUSIONS
  Our results provide new insights into the compartmentalization of the 2 AC isoforms in the regulation of ICa,L in ventricular myocytes. Because caveolae are found in most mammalian cells, the mechanism of β- adrenergic receptor and AC compartmentalization may also be important for β-adrenergic receptor signaling in other cell types.
authors.affiliation: Division of Cardiovascular Medicine, University of California, Davis, Davis, CA 95616, USA.
authors.forename: Valeriy
authors.initials: V
authors.lastname: Timofeyev
authors.forename: Richard E
authors.initials: RE
authors.lastname: Myers
authors.forename: Hyo Jeong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Ryan L
authors.initials: RL
authors.lastname: Woltz
authors.forename: Padmini
authors.initials: P
authors.lastname: Sirish
authors.forename: James P
authors.initials: JP
authors.lastname: Heiserman
authors.forename: Ning
authors.initials: N
authors.lastname: Li
authors.forename: Anil
authors.initials: A
authors.lastname: Singapuri
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: Vladimir
authors.initials: V
authors.lastname: Yarov-Yarovoy
authors.forename: Ebenezer N
authors.initials: EN
authors.lastname: Yamoah
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Nipavan
authors.initials: N
authors.lastname: Chiamvimonvat
mesh_terms: D000262:Adenylyl Cyclases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000595:Amino Acid Sequence; D000818:Animals; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism*; D051244:Caveolin 3 / Q000378:metabolism; D002462:Cell Membrane / Q000201:enzymology; D003198:Computer Simulation; D005455:Fluorescent Antibody Technique; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology*; D007527:Isoenzymes; D007545:Isoproterenol / Q000494:pharmacology; D008564:Membrane Potentials; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D018342:Receptors, Adrenergic, beta-1 / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D000318:Adrenergic beta-Agonists; D020746:Calcium Channels, L-Type; C495548:Cav3 protein, mouse; D051244:Caveolin 3; D007527:Isoenzymes; D018342:Receptors, Adrenergic, beta-1; D010727:Phosphoric Diester Hydrolases; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V; D007545:Isoproterenol
keywords: L-type Ca2+ current; adenylyl cyclase type 5; adenylyl cyclase type 6; adrenergic receptor; calcium channel; ventricular myocytes