Actin Capping Protein

Pyle, W. Glen; Hart, Marilyn C.; Cooper, John A.; Sumandea, Marius P.; Tombe, Pieter P. de; Solaro, R. John

doi:10.1161/01.res.0000024389.03152.22

Cited by 51 publications

(37 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the current study, capping protein ␣1 was highly correlated with HW/BW (Table IV). Capping protein ␤1 was reported to be a critical element in protein kinase C signaling to cardiac myofilaments (74). The current study suggests that capping protein ␣ 1 may play an important role in IGF1R-PI3K(p110␣) signaling to cardiac myocytes.…”

Section: Igf1r Induces Physiological Cardiac Growth Via Pi3k(p110␣)mentioning

confidence: 58%

The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway

McMullen

Shioi

Huang

et al. 2004

Journal of Biological Chemistry

372

325

View full text Add to dashboard Cite

Insulin-like growth factor 1 (IGF1) was considered a potential candidate for the treatment of heart failure. However, some animal studies and clinical trials have questioned whether elevating IGF1 chronically is beneficial. Secondary effects of increased serum IGF1 levels on other tissues may explain these unfavorable results. The aim of the current study was to examine the role of IGF1 in cardiac myocytes in the absence of secondary effects, and to elucidate downstream signaling pathways and transcriptional regulatory effects of the IGF1 receptor (IGF1R). Transgenic mice overexpressing IGF1R in the heart displayed cardiac hypertrophy, which was the result of an increase in myocyte size, and there was no evidence of histopathology. IGF1R transgenics also displayed enhanced systolic function at 3 months of age, and this was maintained at 12-16 months of age. The phosphoinositide 3-kinase (PI3K)-Aktp70S6K1 pathway was significantly activated in hearts from IGF1R transgenics. Cardiac hypertrophy induced by overexpression of IGF1R was completely blocked by a dominant negative PI3K(p110␣) mutant, suggesting IGF1R promotes compensated cardiac hypertrophy in a PI3K(p110␣)-dependent manner. This study suggests that targeting the cardiac IGF1R-PI3K(p110␣) pathway could be a potential therapeutic strategy for the treatment of heart failure.

show abstract

Section: Igf1r Induces Physiological Cardiac Growth Via Pi3k(p110␣)mentioning

confidence: 58%

The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway

McMullen

Shioi

Huang

et al. 2004

Journal of Biological Chemistry

372

325

View full text Add to dashboard Cite

show abstract

“…Desmin phosphorylation by PKC has been linked to myofibril disarray and cardiomyopathy in hamsters, but the isoform(s) of PKC involved and the role of anchoring proteins remain unknown. Very recently, Pyle et al reported that phenylephrine-mediated myofilament/ε-PKC association was decreased in transgenic mice with reduced actin capping protein (CapZ), suggesting that the Z-line-associated CapZ might serve as a useful target in the management of myofilament function by PKC (Pyle et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes

Huang

Walker

2004

Journal of Cell Science

View full text Add to dashboard Cite

Regulatory proteins on muscle filaments are substrates for protein kinase C (PKC) but mechanisms underlying activation and translocation of PKC to this non-membrane compartment are poorly understood. Here we demonstrate that the epsilon isoform of PKC (ε-PKC) activated by arachidonic acid (AA) binds reversibly to cardiac myofibrils with an EC 50 of 86 nM. Binding occurred near the Z-lines giving rise to a striated staining pattern. The delta isoform of PKC (δ-PKC) did not bind to cardiac myofibrils regardless of the activator used, and the alpha isoform (α-PKC) bound only under strong activating conditions. Three established PKC anchoring proteins, filamentous actin (F-actin), the LIM domain protein Cypher-1, and the coatamer protein β′-COP were each tested for their involvement in cytoskeletal anchoring. Factin bound ε-PKC selectively over δ-PKC and α-PKC, but this interaction was readily distinguishable from cardiac myofilament binding in two ways. First, the F-actin/ε-PKC interaction was independent of PKC activation, and second, the synthetic hexapeptide LKKQET derived from the C1 region of ε-PKC effectively blocked ε-PKC binding to F-actin, but was without effect on its binding to cardiac myofilaments. Involvement of Cypher-1 was ruled out on the basis of its absence from detergent-skinned myofibrils that bound ε-PKC, despite its presence in intact cardiac myocytes. The ε-PKC translocation inhibitor peptide EAVSLKPT reduced activated ε-PKC binding to cardiac myofibrils in a concentration dependent manner, suggesting that a RACK2 or a similar protein plays a role in ε-PKC anchoring in cardiac myofilaments.

show abstract

“…They are central to maintaining sarcomere geometry, integrating force, and transmitting tension, so it is reasonable that they could also modulate Ca 2+ -dependent contraction. For example, modifying the Z-disk proteins Cap-Z (reducing expression) or muscle LIM protein (MLP) (acetylation) increases calcium sensitivity (49,50). In skeletal muscle, reducing Z-disk or M-band stiffness reduces calcium sensitivity (51), while genetic mutations in Z-disk proteins result in cardiomyopathy associated with Z-disk destabilization (52) and/or changes in myofilament stiffness and Ca 2+ response (53).…”

Section: Figurementioning

confidence: 99%

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

Kirk¹,

Holewinski²,

Kooij³

et al. 2013

J. Clin. Invest.

Self Cite

View full text Add to dashboard Cite

Cardiac resynchronization therapy (CRT), the application of biventricular stimulation to correct discoordinate contraction, is the only heart failure treatment that enhances acute and chronic systolic function, increases cardiac work, and reduces mortality. Resting myocyte function also increases after CRT despite only modest improvement in calcium transients, suggesting that CRT may enhance myofilament calcium responsiveness. To test this hypothesis, we examined adult dogs subjected to tachypacing-induced heart failure for 6 weeks, concurrent with ventricular dyssynchrony (HF dys ) or CRT. Myofilament force-calcium relationships were measured in skinned trabeculae and/or myocytes. Compared with control, maximal calcium-activated force and calcium sensitivity declined globally in HF dys ; however, CRT restored both. Phosphatase PP1 induced calcium desensitization in control and CRT-treated cells, while HF dys cells were unaffected, implying that CRT enhances myofilament phosphorylation. Proteomics revealed phosphorylation sites on Z-disk and M-band proteins, which were predicted to be targets of glycogen synthase kinase-3β (GSK-3β). We found that GSK-3β was deactivated in HF dys and reactivated by CRT. Mass spectrometry of myofilament proteins from HF dys animals incubated with GSK-3β confirmed GSK-3β-dependent phosphorylation at many of the same sites observed with CRT. GSK-3β restored calcium sensitivity in HF dys , but did not affect control or CRT cells. These data indicate that CRT improves calcium responsiveness of myofilaments following HF dys through GSK-3β reactivation, identifying a therapeutic approach to enhancing contractile function.

show abstract

Actin Capping Protein

Cited by 51 publications

References 43 publications

The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway

The Insulin-like Growth Factor 1 Receptor Induces Physiological Heart Growth via the Phosphoinositide 3-Kinase(p110α) Pathway

Myofilament anchoring of protein kinase C-epsilon in cardiac myocytes

Cardiac resynchronization sensitizes the sarcomere to calcium by reactivating GSK-3β

Contact Info

Product

Resources

About