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Roscovitine, a cyclin-dependent kinase inhibitor, affects several gating mechanisms to inhibit cardiac L-type

V Yarotskyy1, K S Elmslie

  • 1Department of Anesthesiology, Penn State College of Medicine, Penn State University, Hershey, PA 17033, USA.

British Journal of Pharmacology
|August 19, 2007
PubMed
Abstract

Insights

Roscovitine inhibits cardiac L-type calcium channels (Ca((V))1.2) by slowing activation and enhancing inactivation. This purine-based drug may offer new treatments for heart conditions like arrhythmias and hypertension.

Area of Science:

  • Cardiovascular Pharmacology
  • Ion Channel Modulation
  • Drug Discovery

Background:

  • L-type calcium channels (Ca((V))1.2) are critical for cardiac contraction.
  • Roscovitine, a CDK inhibitor, affects Ca((V))1.2 channel function.

Purpose of the Study:

  • To elucidate the mechanism by which roscovitine inhibits Ca((V))1.2 channels.
  • Investigate roscovitine's interaction with L-type calcium channels.

Main Methods:

  • HEK 293 cells expressing Ca((V))1.2 channels were utilized.
  • Whole-cell patch clamp electrophysiology was employed to measure currents.

Main Results:

  • Roscovitine significantly slows Ca((V))1.2 channel activation and enhances voltage-dependent inactivation.
  • The drug acts via an extracellular binding site, independent of kinase activity.
  • Inactivation enhancement involves accelerated inactivation and slowed recovery from inactivation.

Conclusions:

  • Roscovitine inhibits Ca((V))1.2 channels by slowing activation and enhancing inactivation through an extracellular mechanism.
  • Purine-based compounds like roscovitine represent a potential therapeutic strategy for L-channel related diseases.
  • Potential applications include treating cardiac arrhythmias and hypertension.

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