Convergent regulation of skeletal muscle Ca 2+ channels by dystrophin, the actin cytoskeleton, and cAMP-dependent protein kinase
The skeletal muscle L-type Ca 2+ channel (Ca V 1.1), which is responsible for initiating muscle contraction, is regulated by phosphorylation by cAMP-dependent protein kinase (PKA) in a voltage-dependent manner that requires direct physical association between the channel and the kinase mediated thro...
Gespeichert in:
Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2005-03, Vol.102 (11), p.4191-4196 |
---|---|
Hauptverfasser: | , , |
Format: | Artikel |
Sprache: | eng |
Online-Zugang: | Volltext |
Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
Zusammenfassung: | The skeletal muscle L-type Ca
2+
channel (Ca
V
1.1), which is responsible for initiating muscle contraction, is regulated by phosphorylation by cAMP-dependent protein kinase (PKA) in a voltage-dependent manner that requires direct physical association between the channel and the kinase mediated through A-kinase anchoring proteins (AKAPs). The role of the actin cytoskeleton in channel regulation was investigated in skeletal myocytes cultured from wild-type mice,
mdx
mice that lack the cytoskeletal linkage protein dystrophin, and a skeletal muscle cell line, 129 CB
3
. Voltage dependence of channel activation was shifted positively, and potentiation was greatly diminished in
mdx
myocytes and in 129 CB
3
cells treated with the microfilament stabilizer phalloidin. Voltage-dependent potentiation by strong depolarizing prepulses was reduced in
mdx
myocytes but could be restored by positively shifting the stimulus potentials to compensate for the positive shift in the voltage dependence of gating. Inclusion of PKA in the pipette caused a negative shift in the voltage dependence of activation and restored voltage-dependent potentiation in
mdx
myocytes. These results show that skeletal muscle Ca
2+
channel activity and voltage-dependent potentiation are controlled by PKA and microfilaments in a convergent manner. Regulation of Ca
2+
channel activity by hormones and neurotransmitters that use the PKA signal transduction pathway may interact in a critical way with the cytoskeleton and may be impaired by deletion of dystrophin, contributing to abnormal regulation of intracellular calcium concentrations in dystrophic muscle. |
---|---|
ISSN: | 0027-8424 1091-6490 |
DOI: | 10.1073/pnas.0409695102 |