Ginsenoside Rg1 promotes glutamate release via a calcium/calmodulin-dependent protein kinase II-dependent signaling pathway.

Ginseng is one of most extensively used traditional oriental medicines worldwide with beneficial efficacy on cognitive function disorders. Pharmacological researches on its active ingredient--ginsenoside Rg1 revealed that it can improve learning and memory potentially via modulating neurotransmission in the central nervous system, whereas the specific mechanism involved has not been elucidated yet. Our previous studies have indicated that ginsenoside Rb1 could enhance glutamate release via PKA-dependent signaling pathway whereas Rg1 could enhance glutamate release via PKA-independent signaling pathway. In this work we sought to determine the role of another key mediator in neurotransmitter release--calcium/calmodulin-dependent protein kinase II (CaMKII) in the mechanism of Rg1-enhanced glutamate release. Pre-treatment with CaMKII inhibitor KN93 blocked Rg1-induced glutamate release in primary hippocampal neurons. To investigate how CaMKII was involved in this process, the effect of Rg1 on CaMKII was further studied. Rg1 activated CaMKII and subsequently increased phosphorylation level of Synapsin I (Serine(603), a substrate site of CaMKII)--an abundant phosphoprotein essential for regulating neurotransmitter release, which could be blocked by pre-treatment with CaMKII inhibitor KN93. In conclusion, the present study suggests that Rg1 promotes glutamate release potentially via a CaMKII-dependent signaling pathway in which Synapsin I may potentially act as a downstream effector. Combined with our previous study on Rb1, these two studies altogether indicated that different ginsenosides may promote neurotransmitter release via differential signaling pathways. 2010 Elsevier B.V. All rights reserved.