目的本研究采用比较分子力场分析法(comparative molecular field analysis,CoMFA)和比较分子相似性指数分析法(comparative molecular similarity indices analysis,CoMSIA),系统研究了30个1,3-二氢苯并[b][1,4]二氮杂卓-2-酮类非竞争...目的本研究采用比较分子力场分析法(comparative molecular field analysis,CoMFA)和比较分子相似性指数分析法(comparative molecular similarity indices analysis,CoMSIA),系统研究了30个1,3-二氢苯并[b][1,4]二氮杂卓-2-酮类非竞争性代谢型谷氨酸受体2/3(mGluR2/3)拮抗剂的三维定量构效关系。方法通过考察网格点步长对CoMFA研究统计结果和各种分子场组合、网格点步长和衰减因子对CoMSIA研究统计结果的影响,建立了3D-QSAR模型,发现立体场、静电场、疏水场和氢键受体场的组合可得到最佳模型。结果所建立的CoMFA和CoMSIA模型的交叉相关系数q2值分别为0.729和0.713,均具有较强的预测能力。结论利用CoMFA和CoMSIA模型的三维等值线图直观地解释了化合物的构效关系,阐明了化合物结构与生物活性的关系,为进一步结构设计和优化提供了重要依据。展开更多
Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distribu...Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distributed on neurons throughout the central nervous system. These receptors are broadly classified into two main groups, ionotropic glutamate receptors (iGluRs) and metabo-tropic glutamate receptors (mGluRs). Unlike iGluRs, the mGluRs are G-protein coupled receptors that exert their effects on postsynaptic membrane conductance indirectly through the downstream modification of ion channels. A subtype of mGluRs, the Group II mGluRs, are particularly interesting since their activation by glutamate results in a hyperpolarizing response. Thus, glutamate can act potentially as an inhibitory neurotransmitter, by binding to postsynaptic Group II mGluRs. Given the potential importance of these receptors in synaptic processing, the development of the central nervous system, and neurological disorders, we sought to characterize the expression of mGluR2 in the developing neocortex of the mouse. Therefore, we examined the distribution of mGluR2 in the developing cerebral cortex. We found a general caudal to rostral gradient in the expression of these receptors, with ventral cortical regions labeled caudally and dorsal regions labeled rostrally. Limbic regions highly expressed mGluR2 throughout the brain, as did sensory and motor cortical areas. Finally, other non-cortical structures, such as the thalamic reticular nucleus, amygdala, and mammillary bodies were found to have significant expression of the receptor. These results suggest that mGluR2 may play important roles in mediating glutamatergic inhibition in these structures and also could have a role in shaping the development of mature neural networks in the forebrain.展开更多
Identification of host factors that play a key role in viral replication is of great importance for antiviral development.Metabotropic glutamate receptor subtype 2(mGluR2)is the receptor to trigger clathrin-mediated e...Identification of host factors that play a key role in viral replication is of great importance for antiviral development.Metabotropic glutamate receptor subtype 2(mGluR2)is the receptor to trigger clathrin-mediated endocytosis(CME),the major pathway by which influenza virus enters cells.However,other host factors almost certainly involved in the influenza virus CME are largely unknown.Here,we found that the four-transmembrane protein claudin-11 plays an integral part in influenza virus CME.Claudin-11 promotes the dissociation of KCa1.1(potassium calcium-activated channel subfamily M alpha 1)from mGluR2 and,together with mGluR2,is internalized in viruscontaining clathrin-coated pits(CCPs),where it regulates the depolymerization of polymerized F-actin,allowing the CCPs to mature.Importantly,over 60%of claudin-11-silenced mice survived infection with a lethal influenza virus.Our findings advance the understanding of influenza virus infection and provide a promising strategy for the development of host-based antiviral drugs.展开更多
文摘目的本研究采用比较分子力场分析法(comparative molecular field analysis,CoMFA)和比较分子相似性指数分析法(comparative molecular similarity indices analysis,CoMSIA),系统研究了30个1,3-二氢苯并[b][1,4]二氮杂卓-2-酮类非竞争性代谢型谷氨酸受体2/3(mGluR2/3)拮抗剂的三维定量构效关系。方法通过考察网格点步长对CoMFA研究统计结果和各种分子场组合、网格点步长和衰减因子对CoMSIA研究统计结果的影响,建立了3D-QSAR模型,发现立体场、静电场、疏水场和氢键受体场的组合可得到最佳模型。结果所建立的CoMFA和CoMSIA模型的交叉相关系数q2值分别为0.729和0.713,均具有较强的预测能力。结论利用CoMFA和CoMSIA模型的三维等值线图直观地解释了化合物的构效关系,阐明了化合物结构与生物活性的关系,为进一步结构设计和优化提供了重要依据。
文摘Glutamatergic synaptic transmission is an essential component of neural circuits in the central nervous system. Glutamate exerts its effects by binding to various types of glutamate receptors, which are found distributed on neurons throughout the central nervous system. These receptors are broadly classified into two main groups, ionotropic glutamate receptors (iGluRs) and metabo-tropic glutamate receptors (mGluRs). Unlike iGluRs, the mGluRs are G-protein coupled receptors that exert their effects on postsynaptic membrane conductance indirectly through the downstream modification of ion channels. A subtype of mGluRs, the Group II mGluRs, are particularly interesting since their activation by glutamate results in a hyperpolarizing response. Thus, glutamate can act potentially as an inhibitory neurotransmitter, by binding to postsynaptic Group II mGluRs. Given the potential importance of these receptors in synaptic processing, the development of the central nervous system, and neurological disorders, we sought to characterize the expression of mGluR2 in the developing neocortex of the mouse. Therefore, we examined the distribution of mGluR2 in the developing cerebral cortex. We found a general caudal to rostral gradient in the expression of these receptors, with ventral cortical regions labeled caudally and dorsal regions labeled rostrally. Limbic regions highly expressed mGluR2 throughout the brain, as did sensory and motor cortical areas. Finally, other non-cortical structures, such as the thalamic reticular nucleus, amygdala, and mammillary bodies were found to have significant expression of the receptor. These results suggest that mGluR2 may play important roles in mediating glutamatergic inhibition in these structures and also could have a role in shaping the development of mature neural networks in the forebrain.
基金supported by the National Key R&D Program of China(2021YFD1800200,2021YFC2301700)the National Natural Science Foundation of China(32422087,32202773,32192451)+2 种基金the Innovation Program of Chinese Academy of Agricultural Sciences(CAASCSLPDCP-202301,CAAS-CSLPDCP-202401)the earmarked fund for CARS-41the Japan Initiative for Global Research Network on Infectious Diseases from the Japan Agency for Medical Research and Development.
文摘Identification of host factors that play a key role in viral replication is of great importance for antiviral development.Metabotropic glutamate receptor subtype 2(mGluR2)is the receptor to trigger clathrin-mediated endocytosis(CME),the major pathway by which influenza virus enters cells.However,other host factors almost certainly involved in the influenza virus CME are largely unknown.Here,we found that the four-transmembrane protein claudin-11 plays an integral part in influenza virus CME.Claudin-11 promotes the dissociation of KCa1.1(potassium calcium-activated channel subfamily M alpha 1)from mGluR2 and,together with mGluR2,is internalized in viruscontaining clathrin-coated pits(CCPs),where it regulates the depolymerization of polymerized F-actin,allowing the CCPs to mature.Importantly,over 60%of claudin-11-silenced mice survived infection with a lethal influenza virus.Our findings advance the understanding of influenza virus infection and provide a promising strategy for the development of host-based antiviral drugs.
