Compound K, a metabolite of ginsenosides, facilitates spontaneous GABA release onto CA3 pyramidal neurons

Ginsenoside Rb1, a major ingredient of ginseng saponins, can affect various brain functions, including learning and memory. When ingested orally, ginsenoside Rb1 is not found in plasma as well as urine, but its metabolite compound K (ComK) reaches the systemic circulation in animals and human. Nevertheless, the pharmacological actions of ComK are still poorly known. In the present study, we investigated the effect of ComK on GABAergic spontaneous miniature inhibitory postsynaptic currents (mIPSCs) in acutely isolated rat hippocampal CA3 pyramidal neurons using a conventional whole-cell patch-clamp technique. While ComK significantly increased mIPSC frequency in a concentration-dependent manner, it had no effect on the current amplitude, suggesting that ComK acts pre-synaptically to increase the probability of spontaneous GABA release. ComK still increased mIPSC frequency even in a Ca2+ -free external solution, suggesting that the ComK-induced increase spontaneous GABA release is not related to Ca2+ influx from the extracellular space. However, the ComK-induced increase mIPSC frequency was significantly decreased after the blockade of either sarcoplasmic/endoplasmic reticulum Ca2+ -ATPase or Ca2+ release channels. These results strongly suggest that ComK enhances spontaneous GABA release by increasing intraterminal Ca2+ concentration via Ca2+ release from pre-synaptic Ca2+ stores. The ComK-induced modulation of inhibitory transmission onto CA3 pyramidal neurons could have a broad impact on the excitability of CA3 pyramidal neurons and affect the physiological functions mediated by the hippocampus.