Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels.
Circ Res
; 107(6): 747-56, 2010 Sep 17.
Article
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| MEDLINE
| ID: mdl-20671242
ABSTRACT
RATIONALE Sympathetic stimulation of the heart increases the force of contraction and rate of ventricular relaxation by triggering protein kinase (PK)A-dependent phosphorylation of proteins that regulate intracellular calcium. We hypothesized that scaffolding of cAMP signaling complexes by AKAP5 is required for efficient sympathetic stimulation of calcium transients. OBJECTIVE:
We examined the function of AKAP5 in the ß-adrenergic signaling cascade. METHODS ANDRESULTS:
We used calcium imaging and electrophysiology to examine the sympathetic response of cardiomyocytes isolated from wild type and AKAP5 mutant animals. The ß-adrenergic regulation of calcium transients and the phosphorylation of substrates involved in calcium handling were disrupted in AKAP5 knockout cardiomyocytes. The scaffolding protein, AKAP5 (also called AKAP150/79), targets adenylyl cyclase, PKA, and calcineurin to a caveolin 3-associated complex in ventricular myocytes that also binds a unique subpopulation of Ca(v)1.2 L-type calcium channels. Only the caveolin 3-associated Ca(v)1.2 channels are phosphorylated by PKA in response to sympathetic stimulation in wild-type heart. However, in the AKAP5 knockout heart, the organization of this signaling complex is disrupted, adenylyl cyclase 5/6 no longer associates with caveolin 3 in the T-tubules, and noncaveolin 3-associated calcium channels become phosphorylated after ß-adrenergic stimulation, although this does not lead to an enhanced calcium transient. The signaling domain created by AKAP5 is also essential for the PKA-dependent phosphorylation of ryanodine receptors and phospholamban.CONCLUSIONS:
These findings identify an AKAP5-organized signaling module that is associated with caveolin 3 and is essential for sympathetic stimulation of the calcium transient in adult heart cells.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Sistema Nervioso Simpático
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Receptores Adrenérgicos beta
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Canales de Calcio Tipo L
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Miocitos Cardíacos
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Proteínas de Anclaje a la Quinasa A
Tipo de estudio:
Prognostic_studies
/
Risk_factors_studies
Límite:
Animals
Idioma:
En
Revista:
Circ Res
Año:
2010
Tipo del documento:
Article
País de afiliación:
Estados Unidos