Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes

R. Yamasaki, Y. Wu, M. McNabb, M. Greaser, S. Labeit, Hendrikus "Henk" Granzier

Research output: Contribution to journalArticle

213 Citations (Scopus)

Abstract

β-Adrenergic stimulation of cardiac muscle activates protein kinase A (PKA), which is known to phosphorylate proteins on the thin and thick filaments of the sarcomere. Cardiac muscle sarcomeres contain a third filament system composed of titin, and here we demonstrate that titin is also phosphorylated by the β-adrenergic pathway. Titin phosphorylation was observed after β-receptor stimulation of intact cardiac myocytes and incubation of skinned cardiac myocytes with PKA. Mechanical experiments with isolated myocytes revealed that PKA significantly reduces passive tension. In vitro phosphorylation of recombinant titin fragments and immunoelectron microscopy suggest that PKA targets a subdomain of the elastic segment of titin, referred to as the N2B spring element. The N2B spring element is expressed only in cardiac titins, in which it plays an important role in determining the level of passive tension. Because titin-based passive tension is a determinant of diastolic function, these results suggest that titin phosphorylation may modulate cardiac function in vivo.

Original languageEnglish (US)
Pages (from-to)1181-1188
Number of pages8
JournalCirculation Research
Volume90
Issue number11
DOIs
StatePublished - Jun 14 2002
Externally publishedYes

Fingerprint

Connectin
Cyclic AMP-Dependent Protein Kinases
Cardiac Myocytes
Sarcomeres
Phosphorylation
Adrenergic Agents
Myocardium
Immunoelectron Microscopy
Muscle Proteins
Muscle Cells

Keywords

  • β-adrenergic signaling
  • Connectin
  • Diastole
  • Myocyte mechanics
  • Resting tension

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Protein kinase A phosphorylates titin's cardiac-specific N2B domain and reduces passive tension in rat cardiac myocytes. / Yamasaki, R.; Wu, Y.; McNabb, M.; Greaser, M.; Labeit, S.; Granzier, Hendrikus "Henk".

In: Circulation Research, Vol. 90, No. 11, 14.06.2002, p. 1181-1188.

Research output: Contribution to journalArticle

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AU - Wu, Y.

AU - McNabb, M.

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AU - Labeit, S.

AU - Granzier, Hendrikus "Henk"

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N2 - β-Adrenergic stimulation of cardiac muscle activates protein kinase A (PKA), which is known to phosphorylate proteins on the thin and thick filaments of the sarcomere. Cardiac muscle sarcomeres contain a third filament system composed of titin, and here we demonstrate that titin is also phosphorylated by the β-adrenergic pathway. Titin phosphorylation was observed after β-receptor stimulation of intact cardiac myocytes and incubation of skinned cardiac myocytes with PKA. Mechanical experiments with isolated myocytes revealed that PKA significantly reduces passive tension. In vitro phosphorylation of recombinant titin fragments and immunoelectron microscopy suggest that PKA targets a subdomain of the elastic segment of titin, referred to as the N2B spring element. The N2B spring element is expressed only in cardiac titins, in which it plays an important role in determining the level of passive tension. Because titin-based passive tension is a determinant of diastolic function, these results suggest that titin phosphorylation may modulate cardiac function in vivo.

AB - β-Adrenergic stimulation of cardiac muscle activates protein kinase A (PKA), which is known to phosphorylate proteins on the thin and thick filaments of the sarcomere. Cardiac muscle sarcomeres contain a third filament system composed of titin, and here we demonstrate that titin is also phosphorylated by the β-adrenergic pathway. Titin phosphorylation was observed after β-receptor stimulation of intact cardiac myocytes and incubation of skinned cardiac myocytes with PKA. Mechanical experiments with isolated myocytes revealed that PKA significantly reduces passive tension. In vitro phosphorylation of recombinant titin fragments and immunoelectron microscopy suggest that PKA targets a subdomain of the elastic segment of titin, referred to as the N2B spring element. The N2B spring element is expressed only in cardiac titins, in which it plays an important role in determining the level of passive tension. Because titin-based passive tension is a determinant of diastolic function, these results suggest that titin phosphorylation may modulate cardiac function in vivo.

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