Adenylyl cyclase subtype-specific compartmentalization: Differential regulation of L-Type Ca2+ current in ventricular myocytes

Valeriy Timofeyev, Richard E. Myers, Hyo Jeong Kim, Ryan L. Woltz, Padmini Sirish, James P. Heiserman, Ning Li, Anil Singapuri, Tong Tang, Vladimir Yarov-Yarovoy, Ebenezer N. Yamoah, H. Kirk Hammond, Nipavan Chiamvimonvat

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

RATIONALE:: 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. METHODS AND 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 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.

Original languageEnglish (US)
Pages (from-to)1567-1576
Number of pages10
JournalCirculation Research
Volume112
Issue number12
DOIs
StatePublished - Jun 7 2013

Keywords

  • adenylyl cyclase type 5
  • adenylyl cyclase type 6
  • adrenergic receptor
  • calcium channel
  • L-type Ca2+ current
  • ventricular myocytes

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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  • Cite this

    Timofeyev, V., Myers, R. E., Kim, H. J., Woltz, R. L., Sirish, P., Heiserman, J. P., Li, N., Singapuri, A., Tang, T., Yarov-Yarovoy, V., Yamoah, E. N., Hammond, H. K., & Chiamvimonvat, N. (2013). Adenylyl cyclase subtype-specific compartmentalization: Differential regulation of L-Type Ca2+ current in ventricular myocytes. Circulation Research, 112(12), 1567-1576. https://doi.org/10.1161/CIRCRESAHA.112.300370