Ginseng ginsenoside pharmacology in the nervous system: involvement in the regulation of ion channels and receptors

Abstract

Ginseng, the root of Panax ginseng C.A. Meyer, is one of the oldest traditional medicines and is thought to be a tonic. It has been claimed that ginseng may improve vitality and health. Recent studies have advanced ginseng pharmacology and shown that ginseng has various pharmacological effects in the nervous system. Ginsenosides, steroid glycosides extracted from ginseng, were one of the first class of biologically active plant glycosides identified. The diverse pharmacological effects of ginsenosides have been investigated through the regulation of various types of ion channels and receptors in neuronal cells and heterologous expression systems. Ginsenoside Rg3 regulates voltage-gated ion channels such as Ca(2+), K(+), and Na(+) channels, and ligand-gated ion channels such as GABAA, 5-HT3, nicotinic acetylcholine, and N-methyl-D-aspartate (NMDA) receptors through interactions with various sites including channel blocker binding sites, toxin-binding sites, channel gating regions, and allosteric channel regulator binding sites when the respective ion channels or receptors are stimulated with depolarization or ligand treatment. Treatment with ginsenoside Rg3 has been found to stabilize excitable cells by blocking influxes of cations such as Ca(2+) and Na(+), or by enhancing Cl(-) influx. The aim of this review is to present recent findings on the pharmacological functions of the ginsenosides through the interactions with ion channels and receptors. This review will detail the pharmacological applications of ginsenosides as neuroprotective drugs that target ion channels and ligand-gated ion channels.

Keywords: ginseng; ginsenosides; interaction site(s); ion channels and receptors; nervous system.

Figure 1

Structures and main metabolic pathways of 20(S)-ginsenoside Rb1, 20(S)- ginsenoside Rg1, and 20(S)- ginsenoside Rg₃. Ginsenosides are known to be metabolized by human intestinal microflora. This scheme represents the structures and proposed metabolic pathways of 20(S)-ginsenoside Rb1, 20(S)-ginsenoside Rg1, and 20(S)-ginsenoside Rg₃. Bold arrow: main pathway. Dotted arrow: minor or weak pathway. Adapted from Nah et al. (2007).

Figure 2

Topology and sequence alignment of Cav1.2, Nav1.2, and Nav1.4 channels. Ca²⁺ and Na⁺ channels consist of the main α subunit and other auxiliary subunits. α subunit has 4 domains and each domains contain 6 segments. Each segment 4 plays a membrane voltage sensor and segments 5 and 6 form channel pore. The mutated amino acid residues are underlined in the pore-forming segment 6. The underlined specific amino acid residues in these channels are thought to interact with 20(S)-ginsenoside Rg₃ (Rg₃) (Lee et al., ; Choi et al., 2009).

Figure 3

Topology and sequence alignment of BK_Ca, hERG, KCNQ1, and Kv1.4 K⁺ channels. BK_Ca, hERG, KCNQ1, and Kv1.4 K⁺ consist of the main α subunit and auxiliary β subunits. Tetramer of α subunit forms a functional K⁺ channel. α subunit contains 6 segments. Each segment 4 plays a membrane voltage sensor and segments 5 and 6 form channel pore. The mutated amino acid residues are underlined in the pore-forming segment 5 and 6. The underlined specific amino acid residues in those K⁺ channels are thought to interact with 20(S)-ginsenoside Rg₃ near the K⁺ channel “signature sequence” of –TXGYGD– (Lee et al., ; Choi et al., 2010, 2011a,b).

Figure 4

Topology and sequence alignment of α7 nicotinic acetylcholine (nACh) and 5-HT_3A receptors at transmembrane domain 2 (TM2). α7 nACh and 5-HT_3A receptors consist homomeric pentamer. TM2 of each segment forms a channel pore. The underlined specific amino acid residues in those ligand-gated channels are thought to interact with 20(S)-ginsenoside Rg₃ (Lee et al., 2007, 2009).

Figure 5

A schematic illustration on cytosolic Ca²⁺ overload signalings and ginsenoside-mediated attenuation against cytosolic Ca²⁺ overload. This schematic drawing shows that cytosolic Ca²⁺ levels could be elevated in ischemic or traumatic brain injury. The elevation of cytosolic Ca²⁺ levels occurs either via direct activation of voltage-gated Ca²⁺ channels or via depolarization caused by voltage-dependent Na⁺ channel activation and other excitatory ligand-gated ion channels at pre- and post-synaptic sites. The overload of cytosolic Ca²⁺ levels caused by excitatory neurotransmitters or neurotoxins may initiate the persistent activation of Ca²⁺-dependent signaling, resulting in damage, for instance through apoptosis or necrosis. Although ginsenoside has no effects on ion channels and ligand-gated ion channels at rest state of neurons, ginsenoside might exhibit its effects by attenuation of cytosolic Ca²⁺ elevation by abnormal conditions by inhibiting ion channels and receptors (as indicated with “x” in arrow). The detailed explanations were described in text. Ginsenoside exhibits differential regulations on subsets of K⁺ channels. So, one possible hypothesis is that K⁺ channels regulated by ginsenoside might play a balancing role on Ca²⁺ and Na⁺ channel inhibitions by ginsenoside.