Sympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels.

Imagen de Manuel F Navedo
TítuloSympathetic stimulation of adult cardiomyocytes requires association of AKAP5 with a subpopulation of L-type calcium channels.
Publication TypeJournal Article
Year of Publication2010
AutoresC Nichols, B, Rossow, CF, Navedo, MF, Westenbroek, RE, Catterall, WA, Santana, LF, G McKnight, S
JournalCirc Res
Volume107
Issue6
Pagination747-56
Date Published2010 Sep 17
ISSN1524-4571
Palabras claveA Kinase Anchor Proteins, Age Factors, Animals, Calcium Channels, L-Type, Calcium Signaling, Cells, Cultured, Cyclic AMP, Cyclic AMP-Dependent Protein Kinases, Isoproterenol, Mice, Mice, Inbred C57BL, Mice, Knockout, Myocytes, Cardiac, Receptors, Adrenergic, beta, Signal Transduction, Sympathetic Nervous System
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 β-adrenergic signaling cascade.

METHODS AND RESULTS: We used calcium imaging and electrophysiology to examine the sympathetic response of cardiomyocytes isolated from wild type and AKAP5 mutant animals. The β-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 β-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.

DOI10.1161/CIRCRESAHA.109.216127
Alternate JournalCirc. Res.
PubMed ID20671242
PubMed Central IDPMC2981172
Grant ListGM032875 / GM / NIGMS NIH HHS / United States
HL085372 / HL / NHLBI NIH HHS / United States
HL085686 / HL / NHLBI NIH HHS / United States
R01 GM032875 / GM / NIGMS NIH HHS / United States
R01 GM032875-26 / GM / NIGMS NIH HHS / United States
R01 HL085372 / HL / NHLBI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States