Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations of clinic medicine which highlighted an urgent and clear need for more efficacious and fa...Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations of clinic medicine which highlighted an urgent and clear need for more efficacious and faster-acting therapeutic agents to treat patients with MDD,especially those who are refractory to the traditional antidepressants.In the present study,we assessed a novel compound,YY-21,from timosaponin B-Ⅲ derived from sarsasapogenin of Anemarrhenae Rhizoma.We found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 min as determined by excitatory postsynaptic current(EPSC) and field excitatory postsynaptic potential(fEPSP) in medial prefrontal cortex(mPFC) slices.YY-21 demonstrated anxiolytic-like effects following acute administration in animals and reversed the depressivelike and anxiety phenotypes induced by chronic unpredictable mild stress(CMS) with a relatively fast therapeutic onset.Our mechanism research reveals that NMDA receptors and two-pore domain potassium(K2P)(TREK1) channels emerged as new drug targets for faster acting antidepressants.K2 P channels generate leak currents that are responsible the maintenance of resting membrane potential.They are potential targets for the treatment of multiple diseases.Here we identify TKDC,an inhibitor of the TREK subfamily,including TREK1,TREK2 and TRAAK channels.Using TKDC as a chemical probe,a combined study of computations,mutagenesis,and electrophysiology reveal an allosteric ligand-binding site in the extracellular cap of the channels.The molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions cause a blockage of the ion conductive pathway.The identification of the extracellular ligand-binding site is confirmed by the discovery of new inhibitors targeting this site using virtual screening.These results suggest that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.展开更多
Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. ...Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. Formaldehyde induces mis-folding and aggregation of neuronal tau protein, hippocampal neuronal apoptosis, cognitive impairment and loss of memory functions, as well as excitation of peripheral nociceptive neurons in cancer pain models. Intracellular calcium （[Ca2＋]i） is an important intracellular messenger, and plays a key role in many pathological processes. The present study aimed to investigate the effect of formaldehyde on [Ca2＋]i and the possible involvement of N-methyl-D-aspartate receptors （NMDARs） and T-type Ca2＋ channels on the cell membrane. Methods Using primary cultured hippocampal neurons as a model, changes of [Ca2＋]i in the presence of formaldehyde at a low concentration were detected by confocal laser scanning microscopy. Results Formaldehyde at 1 mmol/L approximately doubled [Ca2＋]i. （2R）-amino-5-phosphonopentanoate （AP5, 25 μmol/L, an NMDAR antagonist） and mibefradil （MIB, 1 μmol/L, a T-type Ca2＋ channel blocker）, given 5 min after formaldehyde perfusion, each partly inhibited the formaldehyde-induced increase of [Ca：＋]i, and this inhibitory effect was reinforced by combined application of AP5 and MIB. When applied 3 min before formaldehyde perfusion, AP5 （even at 50μmol/L） did not inhibit the formaldehyde-induced increase of [Ca2＋]i, but MIB （1 μmol/L） significantly inhibited this increase by 70%. Conclusion These results suggest that formaldehyde at a low concentration increases [Ca2＋]i in cultured hippocampal neurons; NMDARs and T-type Ca2＋ channels may be involved in this process.展开更多
The rhizome of Gastrodia elata(GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection...The rhizome of Gastrodia elata(GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection of soluble Aβ1–42oligomers model of LTP injury was used. We investigated the effects of parishin C on the improvement of LTP in soluble Aβ1–42oligomer–injected rats and the underlying electrophysiological mechanisms. Parishin C(i.p. or i.c.v.) significantly ameliorated LTP impairment induced by i.c.v. injection of soluble Aβ1–42oligomers. In cultured hippocampal neurons,soluble Aβ1–42oligomers significantly inhibited NMDAR currents while not affecting AMPAR currents and voltage-dependent currents. Pretreatment with parishin C protected NMDA receptor currents from the damage induced by Aβ. In summary, parishin C improved LTP deficits induced by soluble Aβ1–42oligomers. The protection by parishin C against Aβ-induced LTP damage might be related to NMDA receptors.展开更多
Purpose To identify the structure and the function of NMDA receptors, to understand the modulatory mechanism of some endogenous and exogenous compounds on NMDA receptors, and to provide theoretical basis for developi...Purpose To identify the structure and the function of NMDA receptors, to understand the modulatory mechanism of some endogenous and exogenous compounds on NMDA receptors, and to provide theoretical basis for developing new drugs that modulate NMDA receptors Data sources A total of 24 originally identified articles were selected Study selection A total of 24 articles were selected from several hundred original articles or reviews. The content of selected articles are in accordance with our purpose and the authors are authorized scientists in the study on NMDA receptors.Data extraction After careful review of the selected papers, the meaningful results and conclusions were extracted using scientific criteria and our experience in the research of NMDA receptors.Results NMDA receptor contains at least five subunits. They were designated as the NR1 (ζ1), NR2A (ε1), NR2B (ε2), NR2C (ε3), and NR2D (ε4). A unique feature of NMDA receptor is the requirement for both glutamate and the co agnist glycine for the efficient gating. NMDA receptor is modulated by a number of endogenous and exogenous compounds. Mg 2+ not only blocks the NMDA channel in a voltage dependent manner but also potentiates NMDA induced responses at positive membrane potentials. Na +, K + and Ca 2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. Zn 2+ blocks the NMDA current in a noncompetitive and a voltage independent manner. It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate mediated responses. The activity of NMDA receptors is also strikingly sensitive to the changes in H + concentration, and partially inhibited by the ambient concentration of H + under physiological conditions.Conclusions NMDA receptors are glutamate regulated by ion channels that are permeable to Ca 2+ , Na +, K + and are sensitive to voltage dependent Mg 2+ block This channel complex contributes to excitatory synaptic transmission at sites throughout the brain and the spinal cord,and is modulated by a number of endogenous and exogenous compounds NMDA receptors play a key role in wide range of physiologic and pathologic processes Five NMDA receptor subunits have now been characterized in both rat and mouse brain展开更多
In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hip...In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hippocampus and the cerebral cortices. The modulatory mechanisms of synaptic excitability that are correlated with neuronal tasks are fundamental factors for synaptic plasticity, and they are dependent on intracellular Ca2＋-mediated signaling. In the present review, the A-type K＋ （IA） channel, one of the voltage-dependent cation channels, is considered as a key player in the modulation of Ca2＋ influx through synaptic NMDA receptors and their correlated signaling pathways. The cellular functions of IA channels indicate that they possibly play as integral parts of synaptic and somatic complexes, completing the initiation and stabilization of memory.展开更多
文摘Major depressive disorder(MDD)is a common neuropsychiatric disorder characterized by diverse symptoms.There are big limitations of clinic medicine which highlighted an urgent and clear need for more efficacious and faster-acting therapeutic agents to treat patients with MDD,especially those who are refractory to the traditional antidepressants.In the present study,we assessed a novel compound,YY-21,from timosaponin B-Ⅲ derived from sarsasapogenin of Anemarrhenae Rhizoma.We found that YY-21 obviously increased presynaptic glutamate release and enhanced long-term synaptic activity within 10 min as determined by excitatory postsynaptic current(EPSC) and field excitatory postsynaptic potential(fEPSP) in medial prefrontal cortex(mPFC) slices.YY-21 demonstrated anxiolytic-like effects following acute administration in animals and reversed the depressivelike and anxiety phenotypes induced by chronic unpredictable mild stress(CMS) with a relatively fast therapeutic onset.Our mechanism research reveals that NMDA receptors and two-pore domain potassium(K2P)(TREK1) channels emerged as new drug targets for faster acting antidepressants.K2 P channels generate leak currents that are responsible the maintenance of resting membrane potential.They are potential targets for the treatment of multiple diseases.Here we identify TKDC,an inhibitor of the TREK subfamily,including TREK1,TREK2 and TRAAK channels.Using TKDC as a chemical probe,a combined study of computations,mutagenesis,and electrophysiology reveal an allosteric ligand-binding site in the extracellular cap of the channels.The molecular dynamics simulations suggest that ligand-induced allosteric conformational transitions cause a blockage of the ion conductive pathway.The identification of the extracellular ligand-binding site is confirmed by the discovery of new inhibitors targeting this site using virtual screening.These results suggest that the extracellular cap of a K2P channel can act as a new allosteric site and may serve as a direct drug target.
基金supported by grants from the National Natural Science Foundation of China (81171042,81070893 and 81221002)the Beijing Outstanding Ph.D.Program Mentor Grantthe Specialized Research Fund for Doctoral Programs of Higher Education, China(20110001110058)
文摘Objective Formaldehyde at high concentrations is a contributor to air pollution. It is also an endogenous metabolic product in cells, and when beyond physiological concentrations, has pathological effects on neurons. Formaldehyde induces mis-folding and aggregation of neuronal tau protein, hippocampal neuronal apoptosis, cognitive impairment and loss of memory functions, as well as excitation of peripheral nociceptive neurons in cancer pain models. Intracellular calcium （[Ca2＋]i） is an important intracellular messenger, and plays a key role in many pathological processes. The present study aimed to investigate the effect of formaldehyde on [Ca2＋]i and the possible involvement of N-methyl-D-aspartate receptors （NMDARs） and T-type Ca2＋ channels on the cell membrane. Methods Using primary cultured hippocampal neurons as a model, changes of [Ca2＋]i in the presence of formaldehyde at a low concentration were detected by confocal laser scanning microscopy. Results Formaldehyde at 1 mmol/L approximately doubled [Ca2＋]i. （2R）-amino-5-phosphonopentanoate （AP5, 25 μmol/L, an NMDAR antagonist） and mibefradil （MIB, 1 μmol/L, a T-type Ca2＋ channel blocker）, given 5 min after formaldehyde perfusion, each partly inhibited the formaldehyde-induced increase of [Ca：＋]i, and this inhibitory effect was reinforced by combined application of AP5 and MIB. When applied 3 min before formaldehyde perfusion, AP5 （even at 50μmol/L） did not inhibit the formaldehyde-induced increase of [Ca2＋]i, but MIB （1 μmol/L） significantly inhibited this increase by 70%. Conclusion These results suggest that formaldehyde at a low concentration increases [Ca2＋]i in cultured hippocampal neurons; NMDARs and T-type Ca2＋ channels may be involved in this process.
基金the National Nature Science Foundation of China(No.81373387)National Major Special Project on New Drug Innovation of China(No.2012ZX09301002-004)
文摘The rhizome of Gastrodia elata(GE), a herb medicine, has been used for treatment of neuronal disorders in Eastern Asia for hundreds of years. Parishin C is a major ingredient of GE. In this study, the i.c.v. injection of soluble Aβ1–42oligomers model of LTP injury was used. We investigated the effects of parishin C on the improvement of LTP in soluble Aβ1–42oligomer–injected rats and the underlying electrophysiological mechanisms. Parishin C(i.p. or i.c.v.) significantly ameliorated LTP impairment induced by i.c.v. injection of soluble Aβ1–42oligomers. In cultured hippocampal neurons,soluble Aβ1–42oligomers significantly inhibited NMDAR currents while not affecting AMPAR currents and voltage-dependent currents. Pretreatment with parishin C protected NMDA receptor currents from the damage induced by Aβ. In summary, parishin C improved LTP deficits induced by soluble Aβ1–42oligomers. The protection by parishin C against Aβ-induced LTP damage might be related to NMDA receptors.
文摘Purpose To identify the structure and the function of NMDA receptors, to understand the modulatory mechanism of some endogenous and exogenous compounds on NMDA receptors, and to provide theoretical basis for developing new drugs that modulate NMDA receptors Data sources A total of 24 originally identified articles were selected Study selection A total of 24 articles were selected from several hundred original articles or reviews. The content of selected articles are in accordance with our purpose and the authors are authorized scientists in the study on NMDA receptors.Data extraction After careful review of the selected papers, the meaningful results and conclusions were extracted using scientific criteria and our experience in the research of NMDA receptors.Results NMDA receptor contains at least five subunits. They were designated as the NR1 (ζ1), NR2A (ε1), NR2B (ε2), NR2C (ε3), and NR2D (ε4). A unique feature of NMDA receptor is the requirement for both glutamate and the co agnist glycine for the efficient gating. NMDA receptor is modulated by a number of endogenous and exogenous compounds. Mg 2+ not only blocks the NMDA channel in a voltage dependent manner but also potentiates NMDA induced responses at positive membrane potentials. Na +, K + and Ca 2+ not only pass through the NMDA receptor channel but also modulate the activity of NMDA receptors. Zn 2+ blocks the NMDA current in a noncompetitive and a voltage independent manner. It has been demonstrated that polyamines do not directly activate NMDA receptors, but instead act to potentiate or inhibit glutamate mediated responses. The activity of NMDA receptors is also strikingly sensitive to the changes in H + concentration, and partially inhibited by the ambient concentration of H + under physiological conditions.Conclusions NMDA receptors are glutamate regulated by ion channels that are permeable to Ca 2+ , Na +, K + and are sensitive to voltage dependent Mg 2+ block This channel complex contributes to excitatory synaptic transmission at sites throughout the brain and the spinal cord,and is modulated by a number of endogenous and exogenous compounds NMDA receptors play a key role in wide range of physiologic and pathologic processes Five NMDA receptor subunits have now been characterized in both rat and mouse brain
基金supported by the 2014 Scientific Promotion Program funded by Jeju National University, Korea
文摘In the mammalian brain, information encoding and storage have been explained by revealing the cellular and molecular mechanisms of synaptic plasticity at various levels in the central nervous system, including the hippocampus and the cerebral cortices. The modulatory mechanisms of synaptic excitability that are correlated with neuronal tasks are fundamental factors for synaptic plasticity, and they are dependent on intracellular Ca2＋-mediated signaling. In the present review, the A-type K＋ （IA） channel, one of the voltage-dependent cation channels, is considered as a key player in the modulation of Ca2＋ influx through synaptic NMDA receptors and their correlated signaling pathways. The cellular functions of IA channels indicate that they possibly play as integral parts of synaptic and somatic complexes, completing the initiation and stabilization of memory.
