HERG channel trafficking

Area of Science:

• Cardiovascular Physiology
• Molecular Biology
• Pharmacology

Background:

• Mutations in the hERG/IKr potassium channel cause long QT syndrome, a condition increasing arrhythmia risk.
• Many hERG mutations lead to trafficking defects, causing channel retention in the endoplasmic reticulum (ER).
• The role of protein processing pathways and chaperones in hERG function is largely unknown.

Purpose of the Study:

• To investigate the interaction between cytosolic chaperones and the hERG channel.
• To determine the role of chaperones in hERG folding, maturation, and trafficking.
• To explore hERG/chaperone complexes as potential therapeutic targets.

Main Methods:

• Biochemical assays to detect hERG/chaperone interactions.
• Electrophysiological assays to measure hERG/IKr currents.
• Studies using channel blockers and chaperone inhibitors (e.g., arsenic).

Main Results:

• Cytosolic chaperones Hsp70 and Hsp90 interact with wild-type hERG during its processing.
• Hsp90 inhibition impairs hERG maturation and reduces hERG/IKr currents.
• Trafficking-deficient hERG mutants remain bound to chaperones until trafficking is restored.
• Arsenic disrupts hERG/chaperone complexes, inhibits maturation, and causes ECG abnormalities.

Conclusions:

• Hsp70 and Hsp90 are critical for the proper folding and maturation of wild-type hERG.
• Inhibition of chaperone function leads to acquired long QT syndrome via hERG trafficking defects, not direct channel block.
• hERG/chaperone complexes are novel targets for drugs with potential cardiac liabilities.