Trifluoperazine: a rynodine receptor agonist

Area of Science:

• Cardiovascular Pharmacology
• Molecular Cardiology
• Drug Discovery

Background:

• Trifluoperazine (TFP) is an antipsychotic affecting adrenergic and dopaminergic systems.
• TFP also antagonizes calmodulin (CaM) and alters calsequestrin (CSQ) Ca(2+) binding.
• CaM and CSQ modulate sarcoplasmic reticulum (SR) Ca(2+) release in heart cells.

Purpose of the Study:

• To investigate TFP's effects on cardiac SR Ca(2+) release.
• To examine TFP's actions on single type-2 ryanodine receptor (RyR2) channel activity.
• To determine if TFP's cardiac effects are mediated by CaM or CSQ.

Main Methods:

• Studied TFP effects on SR Ca(2+) release in intact and permeabilized ventricular myocytes.
• Assessed single RyR2 channel activity in lipid bilayers using TFP and nortriptyline (NRT).
• Examined RyR2 activation in the presence and absence of CaM.

Main Results:

• TFP initially activated RyR2-mediated SR Ca(2+) release, leading to SR Ca(2+) depletion.
• TFP and NRT increased RyR2 open probability (Po) in CSQ-free channels.
• RyR2 activation by TFP was independent of CaM, suggesting direct channel interaction.

Conclusions:

• TFP and NRT directly alter RyR2 function.
• This direct action on RyR2 may contribute to drug-induced cardiac side effects.
• The findings suggest novel mechanisms for TFP and NRT cardiac toxicity.