Modulation by testosterone of an endogenous hERG potassium channel current

Area of Science:

• Neuroscience
• Cardiology
• Molecular Biology

Background:

• hERG channels are crucial for cardiac action potential repolarization.
• Gender differences in cardiac repolarization are known, but hormonal regulation of hERG channels is poorly understood.
• Sex hormones, like testosterone, may influence hERG channel function.

Purpose of the Study:

• To investigate the effect of testosterone on endogenous hERG potassium channel current (I(hERG)) in SH-SY5Y neuroblastoma cells.
• To elucidate the mechanisms underlying testosterone's modulation of I(hERG).

Main Methods:

• Whole-cell patch-clamp recordings at 37°C.
• Application of varying testosterone concentrations (10 nM to 1 µM).
• Inhibition studies using androgen receptor antagonist flutamide and PI-3 kinase inhibitor wortmannin.

Main Results:

• Acute application of 10 nM testosterone modestly increased I(hERG) (13-15%).
• High testosterone concentration (1 µM) slightly decreased I(hERG).
• Testosterone's stimulatory effect was blocked by flutamide and wortmannin, indicating androgen receptor and PI-3 kinase involvement.
• Chronic testosterone application also augmented I(hERG) via flutamide-sensitive receptors.

Conclusions:

• Testosterone stimulates hERG K+ channels in neuroblastoma cells.
• The mechanism involves classical androgen receptor activation.
• PI-3 kinase plays a role in the acute testosterone response.
• Findings suggest a novel regulatory pathway for hERG channels by testosterone, with implications for cardiac electrophysiology.