title: Disruption of type 5 adenylyl cyclase enhances desensitization of cyclic adenosine monophosphate signal and increases Akt signal with chronic catecholamine stress.
abstract: BACKGROUND
  Desensitization of the cyclic adenosine monophosphate signal protects cardiac myocytes against catecholamine stress, thus preventing the development of apoptosis. Molecular mechanisms of desensitization have been well studied at the level of adrenergic receptors but less so at the level of the effector enzyme, adenylyl cyclase (AC).
  
  
  RESULTS
  When the effects of long-term (1 to 2 weeks) isoproterenol infusion were compared between type 5 AC-null mice (AC5KO) and wild-type controls, we found that the subsequent responses of left ventricular ejection fraction to sudden intravenous isoproterenol challenge were reduced in AC5KO compared with wild-type mice (ie, physiological desensitization was more effective in AC5KO), consistent with enhanced downregulation of AC catalytic activity in AC5KO. One mechanism for the less effective desensitization in wild-type mice was paradoxical upregulation of type 5 AC protein expression. The number of apoptotic myocytes was similar at baseline but was significantly less in AC5KO after infusion. This was accompanied by a 4-fold greater increase in Bcl-2 and a 3-fold greater increase in phospho-Akt in AC5KO. The latter is most likely mediated by increased membrane localization of phosphoinositide-dependent protein kinase 1, which is known to be inhibited by the cyclic adenosine monophosphate signal.
  
  
  CONCLUSIONS
  The absence of type 5 AC results in more effective desensitization after long-term catecholamine stress and protects against the development of myocyte apoptosis and deterioration of cardiac function, potentially elucidating a novel approach to the therapy of heart failure.
authors: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors: Satoshi
authors: S
authors: Okumura
authors: Dorothy E
authors: DE
authors: Vatner
authors: Reiko
authors: R
authors: Kurotani
authors: Yunzhe
authors: Y
authors: Bai
authors: Shumin
authors: S
authors: Gao
authors: Zengrong
authors: Z
authors: Yuan
authors: Kousaku
authors: K
authors: Iwatsubo
authors: Coskun
authors: C
authors: Ulucan
authors: Jun-ichi
authors: J
authors: Kawabe
authors: Kaushik
authors: K
authors: Ghosh
authors: Stephen F
authors: SF
authors: Vatner
authors: Yoshihiro
authors: Y
authors: Ishikawa
mesh_terms: D000249:Adenosine Monophosphate / Q000378:metabolism*; D000262:Adenylyl Cyclases / Q000235:genetics* / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002395:Catecholamines / Q000378:metabolism*; D002908:Chronic Disease; D015536:Down-Regulation / Q000502:physiology; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism; D006333:Heart Failure / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology; D007527:Isoenzymes / Q000235:genetics* / Q000378:metabolism*; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013312:Stress, Physiological / Q000139:chemically induced / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D000318:Adrenergic beta-Agonists; D002395:Catecholamines; D007527:Isoenzymes; D019253:Proto-Oncogene Proteins c-bcl-2; D000249:Adenosine Monophosphate; D051057:Proto-Oncogene Proteins c-akt; C496568:GRK2 protein, mouse; D054769:G-Protein-Coupled Receptor Kinase 2; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6; C419510:adenylyl cyclase type V; D007545:Isoproterenol