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Isolation of Human Atrial Myocytes for Simultaneous Measurements of Ca2+ Transients and Membrane Currents
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Published on: July 3, 2013

Regulation of cardiac ATP-sensitive potassium channel surface expression by calcium/calmodulin-dependent protein

Ana Sierra1, Zhiyong Zhu, Nicolas Sapay

  • 1Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, Iowa 52242, USA.

The Journal of Biological Chemistry
|December 11, 2012
PubMed

Insights

Calcium/calmodulin-dependent protein kinase II (CaMKII) activation reduces cardiac ATP-sensitive potassium (K(ATP)) channels by promoting their internalization. This phosphorylation-dependent process impacts channel function and cardiac energy homeostasis.

Area of Science:

  • Cardiovascular Biology
  • Cellular Physiology
  • Molecular Cardiology

Background:

  • Cardiac ATP-sensitive potassium (K(ATP)) channels are crucial for cardiomyocyte energy balance and injury resistance.
  • Their membrane expression is vital for function, but regulation by signaling pathways remains incompletely understood.

Purpose of the Study:

  • To investigate how calcium/calmodulin-dependent protein kinase II (CaMKII) activation affects cardiac K(ATP) channel surface expression and function.
  • To elucidate the molecular mechanisms linking CaMKII signaling to K(ATP) channel regulation.

Main Methods:

  • Real-time monitoring of K(ATP) channel current density in isolated hearts and cardiomyocytes.
  • Immunohistochemistry and biotinylation studies in wild-type and transgenic mice, and HEK cells.
  • Molecular modeling to predict protein-protein interactions.

Main Results:

  • CaMKII activation induced dynamin-dependent internalization of K(ATP) channels.
  • This process required phosphorylation of specific threonine residues (180 and 224) on the Kir6.2 subunit and an intact YSKF motif.
  • Molecular modeling suggested a direct interaction between phosphorylated Kir6.2 and the AP2 endocytosis adaptor protein.

Conclusions:

  • Calcium-dependent CaMKII activation phosphorylates Kir6.2, promoting cardiac K(ATP) channel endocytosis.
  • This mechanism links CaMKII signaling to K(ATP) channel surface expression, impacting cardiac energy homeostasis.
  • Identified phosphorylation sites and endocytosis motifs offer potential therapeutic targets for improving cardiac stress resistance.

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