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Protein kinase A modulation of CaV1.4 calcium channels

Lingjie Sang1, Ivy E Dick1, David T Yue1,2

  • 1Calcium Signals Laboratory, Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Ross Building, Room 713, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.

Nature Communications
|July 27, 2016
PubMed

Insights

Protein kinase A (PKA) phosphorylation modulates CaV1.4 L-type calcium channels in the visual system. This mechanism enhances channel activity and inactivation, and may apply to other L-type channels.

Area of Science:

  • Molecular and Cellular Biology
  • Neuroscience
  • Cardiovascular Physiology

Background:

  • L-type Ca(2+) channels are critical in cardiac, skeletal muscle, and neurological functions.
  • Protein kinase A (PKA) regulates L-type Ca(2+) channels, particularly CaV1.2 in the heart.
  • CaV1.4 L-type Ca(2+) channels, vital for the visual system, are poorly understood regarding PKA regulation.

Purpose of the Study:

  • To investigate the role of PKA phosphorylation in modulating CaV1.4 L-type Ca(2+) channels.
  • To elucidate the specific mechanism of PKA action on CaV1.4 channels.
  • To explore the potential generalizability of this regulatory mechanism across L-type channel subtypes.

Main Methods:

  • Electrophysiological recordings in heterologous systems.
  • Site-directed mutagenesis to study the inhibitor of Ca(2+)-dependent inactivation (ICDI) motif.
  • Biochemical assays to assess calmodulin binding.

Main Results:

  • PKA phosphorylation of the ICDI motif in CaV1.4 channels was identified.
  • Phosphorylation increases calmodulin occupancy, enhancing channel open probability (PO) and Ca(2+)-dependent inactivation.
  • Transferring the ICDI1.4 motif to CaV1.3 or CaV1.2 channels conferred PKA modulation, suggesting broader applicability.

Conclusions:

  • PKA-dependent regulation of CaV1.4 channels occurs via the ICDI motif, impacting channel function and inactivation.
  • This mechanism is crucial for visual system function and may be conserved across the L-type Ca(2+) channel family.
  • The findings reveal a novel regulatory pathway for L-type Ca(2+) channels with implications for various physiological systems.

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