Activation of lysophosphatidic acid receptor by gintonin inhibits Kv1.2 channel activity: Involvement of tyrosine kinase and receptor protein tyrosine phosphatase α

Lee, Jun-Ho; Choi, Sun-Hye; Lee, Byung-Hwan; Hwang, Sung‐Hee; Kim, Hyeonjoong; Rhee, Jeehae; Chung, ChiHye; Nah, Seung‐Yeol

doi:10.1016/j.neulet.2013.05.048

Cited by 17 publications

(14 citation statements)

References 19 publications

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“…This observation is consistent with previous reports in artificial expressing systems Nah 2012;. The application of LPA agonists is also known to activate the LPAR4-mediated Rho-signaling pathway, thereby accumulating cAMP in cultured B103 cells, implying that LPAR4 could mediate gintonin-induced synaptic enhancement effects as shown with LPAR1-3 (Lee et al 2007).…”

Section: Discussionsupporting

confidence: 93%

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

Park

Kim

Rhee

et al. 2015

Journal of Neurophysiology

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Park H, Kim S, Rhee J, Kim HJ, Han JS, Nah SY, Chung C. Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses. J Neurophysiol 113: 1493-1500, 2015. First published December 10, 2014 doi:10.1152/jn.00667.2014 is one of the well-characterized, ubiquitous phospholipid molecules. LPA exerts its effect by activating G protein-coupled receptors known as LPA receptors (LPARs). So far, LPAR signaling has been critically implicated during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons. In adult brains, LPARs seem to participate in cognitive as well as emotional learning and memory. Recent studies using LPAR1-deficient mice reported impaired performances in a number of behavioral tasks, including the hippocampus-dependent spatial memory and fear conditioning tests. Nevertheless, the effect of LPAR activation in the synaptic transmission of central synapses after the completion of embryonic development has not been investigated. In this study, we took advantage of a novel extracellular agonist for LPARs called gintonin to activate LPARs in adult brain systems. Gintonin, a recently identified active ingredient in ginseng, has been shown to activate LPARs and mobilize Ca 2ϩ in an artificial cell system. We found that the activation of LPARs by application of gintonin acutely enhanced both excitatory and inhibitory transmission in central synapses, albeit through tentatively distinct mechanisms. Gintonin-mediated LPAR activation primarily resulted in synaptic enhancement and an increase in neuronal excitability in a phospholipase C-dependent manner. Our findings suggest that LPARs are able to directly potentiate synaptic transmission in central synapses when stimulated exogenously. Therefore, LPARs could serve as a useful target to modulate synaptic activity under pathological conditions, including neurodegenerative diseases. synaptic potentiation; lysophosphatidic acid receptor; ginseng; gintonin LYSOPHOSPHATIDIC ACID (LPA) is one of the well-characterized, ubiquitous phospholipids and exerts its effect by activating G protein-coupled receptors known as LPA receptors 1-5 (LPAR1-LPAR5; Choi et al. 2010). A number of studies have shown that LPAR signaling plays a critical role during early development stages, including the regulation of synapse formation and the morphology of cortical and hippocampal neurons (Dubin et al.

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Section: Discussionsupporting

confidence: 93%

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

Park

Kim

Rhee

et al. 2015

Journal of Neurophysiology

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“…However, ion channel modulation can occur through other mechanisms, such as direct gating by cyclic nucleotides [73,74] or G proteins [75], or direct and indirect effects of tyrosine kinases [76,77]. All these mechanisms share the common theme that different phosphorylation sites control different aspects of channel gating.…”

Section: Neuromodulation Of Neuronal Excitabilitymentioning

confidence: 99%

Neuromodulation of neurons and synapses

Nadim

Bucher

2014

Current Opinion in Neurobiology

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Neuromodulation underlies the flexibility of neural circuit operation and behavior. Individual neuromodulators can have divergent actions in a neuron by targeting multiple physiological mechanisms. Conversely, multiple neuromodulators may have convergent actions through overlapping targets. Additionally, the divergent and convergent neuromodulator actions can be unambiguously synergistic or antagonistic. Neuromodulation often entails balanced adjustment of nonlinear membrane and synaptic properties by targeting ion channel and synaptic dynamics rather than just excitability or synaptic strength. In addition, neuromodulators can exert effects at multiple timescales, from short-term adjustments of neuron and synapse function to persistent long-term regulation. This short review summarizes some highlights of the diverse actions of neuromodulators on ion channel and synaptic properties.

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“…By contrast, ginsenoside Rg 3 inhibits voltage-dependent Kv1.4 and Kv4.2 in human cells, but not Kv1.3, Kv1.5, and Kv2.1 expressed in Xenopus laevis oocytes (Jeong et al, 2004; Lee et al, 2013c), indicating that ginsenoside Rg 3 differentially regulates Kv channel subtypes. The regulatory effect of ginsenoside Rg 3 on Kv1.4 channel activity has been found to be strongly dependent on the extracellular K + concentration, by shifting the ginsenoside Rg 3 concentration-response curve to the right, indicating that ginsenoside Rg 3 competes with extracellular [K + ] for the same interaction site(s) (Lee et al, 2008a).…”

Section: Ginsenoside Pharmacology Through the Interaction With Voltagmentioning

confidence: 99%

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

Nah

2014

Front. Physiol.

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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 Ca2+, 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 Ca2+ 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.

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Activation of lysophosphatidic acid receptor by gintonin inhibits Kv1.2 channel activity: Involvement of tyrosine kinase and receptor protein tyrosine phosphatase α

Cited by 17 publications

References 19 publications

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

Synaptic enhancement induced by gintonin via lysophosphatidic acid receptor activation in central synapses

Neuromodulation of neurons and synapses

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

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