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

42 Citations (Scopus)

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

Fingerprint

Adenylyl Cyclases
Muscle Cells
Protein Isoforms
Adrenergic Receptors
Caveolin 3
Caveolae
Phosphoric Diester Hydrolases
Cell Membrane
Caveolins
Second Messenger Systems
Sequence Homology
Cardiac Myocytes
Knockout Mice
Proteins
Heart Failure
Adenosine Triphosphate

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

Cite this

Adenylyl cyclase subtype-specific compartmentalization : Differential regulation of L-Type Ca2+ current in ventricular myocytes. / Timofeyev, Valeriy; Myers, Richard E.; Kim, Hyo Jeong; Woltz, Ryan L.; Sirish, Padmini; Heiserman, James P.; Li, Ning; Singapuri, Anil; Tang, Tong; Yarov-Yarovoy, Vladimir; Yamoah, Ebenezer N.; Hammond, H. Kirk; Chiamvimonvat, Nipavan.

In: Circulation Research, Vol. 112, No. 12, 07.06.2013, p. 1567-1576.

Research output: Contribution to journalArticle

Timofeyev, V, Myers, RE, Kim, HJ, Woltz, RL, Sirish, P, Heiserman, JP, Li, N, Singapuri, A, Tang, T, Yarov-Yarovoy, V, Yamoah, EN, Hammond, HK & Chiamvimonvat, N 2013, 'Adenylyl cyclase subtype-specific compartmentalization: Differential regulation of L-Type Ca2+ current in ventricular myocytes', Circulation Research, vol. 112, no. 12, pp. 1567-1576. https://doi.org/10.1161/CIRCRESAHA.112.300370
Timofeyev, Valeriy ; Myers, Richard E. ; Kim, Hyo Jeong ; Woltz, Ryan L. ; Sirish, Padmini ; Heiserman, James P. ; Li, Ning ; Singapuri, Anil ; Tang, Tong ; Yarov-Yarovoy, Vladimir ; Yamoah, Ebenezer N. ; Hammond, H. Kirk ; Chiamvimonvat, Nipavan. / Adenylyl cyclase subtype-specific compartmentalization : Differential regulation of L-Type Ca2+ current in ventricular myocytes. In: Circulation Research. 2013 ; Vol. 112, No. 12. pp. 1567-1576.
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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.",
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T2 - Differential regulation of L-Type Ca2+ current in ventricular myocytes

AU - Timofeyev, Valeriy

AU - Myers, Richard E.

AU - Kim, Hyo Jeong

AU - Woltz, Ryan L.

AU - Sirish, Padmini

AU - Heiserman, James P.

AU - Li, Ning

AU - Singapuri, Anil

AU - Tang, Tong

AU - Yarov-Yarovoy, Vladimir

AU - Yamoah, Ebenezer N.

AU - Hammond, H. Kirk

AU - Chiamvimonvat, Nipavan

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N2 - 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.

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KW - adenylyl cyclase type 6

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KW - calcium channel

KW - L-type Ca2+ current

KW - ventricular myocytes

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