Received for publication June 20, 2006.
Revised September 16, 2006.
Accepted for publication September 19, 2006.

Ginsenoside Re, a Main Phytosterol of Panax Ginseng, Activates Cardiac Potassium Channels via a Non-Genomic Pathway of Sex Hormones

Abstract

Ginseng root is one of the most popular herbs throughout the world in the belief that it is a panacea and promotes longevity. In cardiovascular system, it has been used as a medicine that protects against cardiac ischemia, major cause of death in the West. We have previously demonstrated that ginsenoside Re, a main phytosterol of Panax ginseng, inhibits Ca²⁺ accumulation in mitochondria during cardiac ischemia/reperfusion, which is attributable to nitric oxide (NO)-induced Ca²⁺ channel inhibition and K⁺ channel activation in cardiac myocytes. Here, we provide compelling evidence that ginsenoside Re activates endothelial NO synthase (eNOS) to release NO, resulting in activation of the slowly activating delayed rectifier K⁺ current. The eNOS activation occurs via a non-genomic pathway of each of androgen receptor (AR), estrogen receptor- (ER), and progesterone receptor (PR), in which c-Src, phosphoinositide 3- kinase, Akt, and eNOS are sequentially activated. However, ginsenoside Re does not stimulate proliferation of androgen-responsive LNCaP cells and estrogen- responsive MCF-7 cells, implicating that ginsenoside Re does not activate a genomic pathway of sex hormone receptors. Fluorescence resonance energy transfer (FRET) experiments with a probe, SCCoR (single cell co- activator recruitment), indicate that the lack of genomic action is attributable to failure of co- activator recruitment. Thus, ginsenoside Re acts as a specific agonist for the non-genomic pathway of sex steroid receptors, and NO released from activated eNOS underlies cardiac K⁺ channel activation and protection against ischemia-reperfusion injury.

Key words: Ion channel regulation, Func. analysis receptor/ion channel mutants

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