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
Two-pore domain potassium (K2P) channels gate primarily within the selectivity filter, termed ‘C-type’ gating. Due to the lack of structural insights into the nonconductive (closed) state, ‘C-type’ gating mechanis...Two-pore domain potassium (K2P) channels gate primarily within the selectivity filter, termed ‘C-type’ gating. Due to the lack of structural insights into the nonconductive (closed) state, ‘C-type’ gating mechanisms remain elusive. Here, molecular dynamics (MD) simulations on TREK-1, a K2P channel, revealed that M4 helix movements induce filter closing in a novel ‘deeper-down’ structure that represents a ‘C-type’ closed state. The ‘down’ structure does not represent the closed state as previously proposed and instead acts as an intermediate state in gating. The study identified the allosteric ‘seesaw’ mechanism of M4 helix movements in modulating filter closing. Finally, guided by this recognition of K2P gating mechanisms, MD simulations revealed that gain-of-function mutations and small-molecule activators activate TREK-1 by perturbing state transitions from open to closed states. Together, we reveal a ‘C-type’ closed state and provide mechanical insights into gating procedures and allosteric regulations for K2P channels.展开更多
With the support of the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Yang Huaiyu(阳怀宇)from the East China Normal University and Prof.Li Yang(李扬)from Shangha...With the support of the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Yang Huaiyu(阳怀宇)from the East China Normal University and Prof.Li Yang(李扬)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences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This work was supported in part by the Ministry of Science and Technology(2018YFA0508100 to Q.Z.and J.G.)the National Natural Science Foundation of China(31800699 to Q.Z.)the Fundamental Research Funds for the Central Universities,and the‘XingFuZhiHua’funding of ECNU(44300-19311-542500/006 to H.Y.).
文摘Two-pore domain potassium (K2P) channels gate primarily within the selectivity filter, termed ‘C-type’ gating. Due to the lack of structural insights into the nonconductive (closed) state, ‘C-type’ gating mechanisms remain elusive. Here, molecular dynamics (MD) simulations on TREK-1, a K2P channel, revealed that M4 helix movements induce filter closing in a novel ‘deeper-down’ structure that represents a ‘C-type’ closed state. The ‘down’ structure does not represent the closed state as previously proposed and instead acts as an intermediate state in gating. The study identified the allosteric ‘seesaw’ mechanism of M4 helix movements in modulating filter closing. Finally, guided by this recognition of K2P gating mechanisms, MD simulations revealed that gain-of-function mutations and small-molecule activators activate TREK-1 by perturbing state transitions from open to closed states. Together, we reveal a ‘C-type’ closed state and provide mechanical insights into gating procedures and allosteric regulations for K2P channels.
文摘With the support of the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Yang Huaiyu(阳怀宇)from the East China Normal University and Prof.Li Yang(李扬)from Shanghai Institute of Materia Medica,Chinese Academy of Sciences
