Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling

Tong Tang, Mei Hua Gao, N. Chin Lai, Amy L. Firth, Toshiyuki Takahashi, Tracy Guo, Jason X.J. Yuan, David M. Roth, H. Kirk Hammond

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

BACKGROUND: Adenylyl cyclases (ACs) are a family of effector molecules for G-protein-coupled receptors. The 2 ACs most abundantly expressed in cardiac myocytes are types 5 (AC5) and 6 (AC6), which have 65% amino acid homology. It has been speculated that coexpression of 2 AC types in cardiac myocytes represents redundancy, but the specific role of AC6 in cardiac physiology and its differences from AC5 remain to be defined. METHODS AND RESULTS: We generated transgenic mice with targeted deletion of AC6. Deletion of AC6 was associated with reduced left ventricular contractile function (P=0.026) and relaxation (P=0.041). The absence of AC6 was associated with a 48% decay in β-adrenergic receptor-stimulated cAMP production in cardiac myocytes (P=0.003) and reduced protein kinase A activity (P=0.015). In addition, phospholamban phosphorylation was reduced (P=0.015), sarcoplasmic reticulum Ca-ATPase activity was impaired (P<0.0001), and cardiac myocytes showed marked abnormalities in calcium transient formation (P=0.001). CONCLUSIONS: The combination of impaired cardiac cAMP generation and calcium handling that result from AC6 deletion underlies abnormalities in left ventricular function. The biochemical and physiological consequences of AC6 deletion reveal it to be an important effector molecule in the adult heart, serving unique biological functions not replicated by AC5.

Original languageEnglish (US)
Pages (from-to)61-69
Number of pages9
JournalCirculation
Volume117
Issue number1
DOIs
StatePublished - Jan 2008

Keywords

  • Calcium
  • Heart contractility
  • Knockout mice
  • Receptors, adrenergic, beta

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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    Tang, T., Gao, M. H., Lai, N. C., Firth, A. L., Takahashi, T., Guo, T., Yuan, J. X. J., Roth, D. M., & Hammond, H. K. (2008). Adenylyl cyclase type 6 deletion decreases left ventricular function via impaired calcium handling. Circulation, 117(1), 61-69. https://doi.org/10.1161/CIRCULATIONAHA.107.730069