There is an urgent need to break through the trade-off between proton conductivity and ion selectivity of proton exchange membrane(PEM)in vanadium flow battery(VFB).Proton channels in PEM are the key to controlling th...There is an urgent need to break through the trade-off between proton conductivity and ion selectivity of proton exchange membrane(PEM)in vanadium flow battery(VFB).Proton channels in PEM are the key to controlling the ion sieving and proton conductivity in VFB.Herein,two types of proton channels are reconstructed in the hybrid membrane via introducing modified Zr-MOFs(IM-UIO-66-AS)into SPEEK matrix.Internal proton channels in IM-UIO-66-AS and interfacial proton channels between grafted imidazole groups on Zr-MOFs and SPEEK greatly improve the conductivity of the IM-UIO-66-AS/SPEEK hybrid membrane.More importantly,both reconstructed proton channels block the vanadium-ion permeation to realize enhanced ion selectivity according to the size sieving and Donnan exclusion effects,respectively.Moreover,the hybrid membrane exhibits good mechanical property and dimensional stability.Benefiting from such rational design,a VFB loading with the optimized membrane exhibits enhanced voltage efficiency of 79.9%and outstanding energy efficiency of 79.6%at 200 m A cm^(-2),and keeps a notable cycle stability for 300 cycles in the long-term cycling test.Therefore,this study provides inspiration for preparing next-generation PEMs with high ion selectivity and proton conductivity for VFB application.展开更多
Construction of proton transport channels in metal-organic frameworks(MOFs)with simple synthesis processes,high proton conductivities and good performance stabilities has been of great interest for proton exchange mem...Construction of proton transport channels in metal-organic frameworks(MOFs)with simple synthesis processes,high proton conductivities and good performance stabilities has been of great interest for proton exchange membrane fuel cell(PEMFC).Herein,we mimic the proton transport behavior of amino acid residues in bacteriorhodopsin,select UiO-66-COOH as the host,glycine and aspartic acid as the functional vip molecules,and then functionalize the MOF framework with amino acids to obtain biomimetic proton transport channels.This strategy endows UiO-66-COOH-Asp a high proton conductivity of 1.19×10^(-2)S/cm at 70℃and 98%RH,excellent cycle stability of performances and performance durability,which can be comparable to the reported MOFs-based proton conductors.Moreover,the proton conduction mechanism in UiO-66-COOH-Asp is elaborated in detail due to its visual structure,which is also one of the advantages of adopting MOFs as research platform,making it possible to optimize the structure-activity relationship of advanced materials.Notably,this strategy has clear objectives and simple synthesis,which has made certain contributions to both theoretical research and future industrial production of proton conductors.展开更多
This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpu...This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory,reduces microglial production of interleukin-1βand tumour necrosis factor alpha,and decreases apoptosis of oligodendrocyte progenitor cells.Furthermore,electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice,remaining within normal limits.In addition,Hv1 knockdown mitigated interleukin-1βsecretion and suppressed ferroptosis markers(ferritin heavy chain/ferritin light chain,CCAAT/enhancer binding protein homologous protein,glucose-regulated protein 78,etc.)in vitro,suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination.We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models,longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.展开更多
BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)...BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.展开更多
The distinctions between locality and non-locality as well as causality and excess correlation may be related to coupling between increments of space-time or to the total space-time within the universe as a unit. The ...The distinctions between locality and non-locality as well as causality and excess correlation may be related to coupling between increments of space-time or to the total space-time within the universe as a unit. The most likely candidates for the latter are the proton and the electron when related by Minkowski’s space-time. When two velocities: light in a vacuum for locality and the “entanglement” velocity based upon parameters that define the universe for non-locality, are considered the two times required to produce identities for the -v<sup>2</sup>t<sup>2</sup> components are frequencies whose energies approximate the neutral hydrogen line (primarily associated with shifts in electron spin direction) and the mass equivalence of a proton. The values for the additional three spatial dimensions required to produce a solution whose square root is not imaginary and greater than zero are within the domains of the surface areas of the human cerebrum. Detailed calculations converge to show that the proportions of energy that represent the electron’s Compton energy and the proton’s mass equivalent may be central to the condition of excess correlation within the cerebral volume. Proton channels within the neuronal cell plasma membranes whose pH-dependent specific currents produce the required magnetic field strengths could be the physical substrates by which excess correlations between brain activities of human subjects separated by non-local distances might occur. If protons are considered as the basic Eddington (number) units of the universe then Mach’s principle that any component of the universe is determined by all of its components may be testable empirically.展开更多
After spinal cord injury,microglia as the first responders to the lesion display both beneficial and detrimental characteristics.Activated microglia phagocyte and eliminate cell debris,release cytokines to recruit per...After spinal cord injury,microglia as the first responders to the lesion display both beneficial and detrimental characteristics.Activated microglia phagocyte and eliminate cell debris,release cytokines to recruit peripheral immune cells to the injury site.Excessively activated microglia can aggravate the secondary damage by producing extravagant reactive oxygen species and pro-inflammatory cytokines.Recent studies demonstrated that the voltage-gated proton channel Hv1 is selectively expressed in microglia and regulates microglial activation upon injury.In mouse models of spinal cord injury,Hv1 deficiency ameliorates microglia activation,resulting in alleviated production of reactive oxygen species and pro-inflammatory cytokines.The reduced secondary damage subsequently decreases neuronal loss and correlates with improved locomotor recovery.This review provides a brief historical perspective of advances in investigating voltage-gated proton channel Hv1 and home in on microglial Hv1.We discuss recent studies on the roles of Hv1 activation in pathophysiological activities of microglia,such as production of NOX-dependent reactive oxygen species,microglia polarization,and tissue acidosis,particularly in the context of spinal cord injury.Further,we highlight the rationale for targeting Hv1 for the treatment of spinal cord injury and related disorders.展开更多
Ion conductive membranes(ICMs)with highly conductive proton selectivity are of significant importance and greatly desired for energy storage devices.However,it is extremely challenging to construct fast proton-selecti...Ion conductive membranes(ICMs)with highly conductive proton selectivity are of significant importance and greatly desired for energy storage devices.However,it is extremely challenging to construct fast proton-selective transport channels in ICMs.Herein,a membrane with highly conductive proton selectivity was fabricated by incorporating porous carbon sieving nanospheres with a hollow structure(HCSNs)in a polymer matrix.Due to the precise ion sieving ability of the microporous carbon shells and the fast proton transport through their accessible internal cavities,this advanced membrane presented a proton conductivity(0.084 S·cm^(-1))superior to those of a commercial Nation 212(N212)membrane(0.033S·cm^(-1))and a pure polymer membrane(0.049 S·cm^(-1)).The corresponding proton selectivity of the membrane(6.68×10^(5) S·min·cm^(-3))was found to be enhanced by about 5.9-fold and 4.3-fold,respectively,compared with those of the N212 membrane(1.13×10^(5) S·min·cm^(-3))and the pure membrane(1.56×10^(5) S·min·cm^(-3)).Low-field nuclear magnetic resonance(LF-NMR)clearly revealed the fast protonselective transport channels enabled by the HCSNs in the polymeric membrane.The proposed membrane exhibited an outstanding energy efficiency(EE)of 84%and long-term stability over 1400 cycles with a0.065%capacity decay per cycle at 120 mA·cm^(-2) in a typical vanadium flow battery(VFB)system.展开更多
The feasibility of producing superheavy nuclei in proton evaporation channels was systematically studied within the dinuclear system(DNS)model.Due to the Z=114 proton-shell,one can synthesize Fl isotopes in proton eva...The feasibility of producing superheavy nuclei in proton evaporation channels was systematically studied within the dinuclear system(DNS)model.Due to the Z=114 proton-shell,one can synthesize Fl isotopes in proton evaporation channels.We only considered the case of evaporating one proton first and then n neutrons in this work,other cases were ignored due to the small cross-section.The production cross sections of unknown isotopes ^(290,291)Fl in ^(38)S+^(255)Es reaction are the highest compared with ^(50)Ti+^(243)Np and ^(54)Cr+^(239)Pa reactions,and the maximum cross sections are 1.1 and 15.1 pb,respectively.^(42)S+^(254)Es is a promising candidate to approach the island of stability as the radioactive beam facilities are upgraded in the future,and the production cross sections of ^(291−294)Fl in that reaction are estimated to be 3.2,6.0,4.0,and 0.1 pb,respectively.展开更多
The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms b...The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway.This review provides a detailed examination of the structural features of cGAS and STING proteins,with a particular emphasis on their activation and inhibition mechanisms.We also discuss the novel discovery of STING functioning as an ion channel.Furthermore,we offer an overview of key agonists and antagonists of cGAS and STING,shedding light on their mechanisms of action.Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.展开更多
The M2 proteins of influenza A and B virus,AM2 and BM2,respectively,are transmembrane proteins that oligomerize in the viral membrane to form proton-selective channels.Proton conductance of the M2 proteins is required...The M2 proteins of influenza A and B virus,AM2 and BM2,respectively,are transmembrane proteins that oligomerize in the viral membrane to form proton-selective channels.Proton conductance of the M2 proteins is required for viral replication;it is believed to equilibrate pH across the viral membrane during cell entry and across the trans-Golgi membrane of infected cells during viral maturation.In addition to the role of M2 in proton conductance,recent mutagenesis and structural studies suggest that the cytoplasmic domains of the M2 proteins also play a role in recruiting the matrix proteins to the cell surface during virus budding.As viral ion channels of minimalist architecture,the membrane-embedded channel domain of M2 has been a model system for investigating the mechanism of proton conduction.Moreover,as a proven drug target for the treatment of influenza A infection,M2 has been the subject of intense research for developing new anti-flu therapeutics.AM2 is the target of two anti-influenza A drugs,amantadine and rimantadine,both belonging to the adamantane class of compounds.However,resistance of influenza A to adamantane is now widespread due to mutations in the channel domain of AM2.This review summarizes the structure and function of both AM2 and BM2 channels,the mechanism of drug inhibition and drug resistance of AM2,as well as the development of new M2 inhibitors as potential anti-flu drugs.展开更多
基金supported by the National Natural Science Foundation of China(Grant No.21975267)the Central Guidance on Local Science and Technology Development Fund of Liaoning Province(No:2022JH6/100100001)。
文摘There is an urgent need to break through the trade-off between proton conductivity and ion selectivity of proton exchange membrane(PEM)in vanadium flow battery(VFB).Proton channels in PEM are the key to controlling the ion sieving and proton conductivity in VFB.Herein,two types of proton channels are reconstructed in the hybrid membrane via introducing modified Zr-MOFs(IM-UIO-66-AS)into SPEEK matrix.Internal proton channels in IM-UIO-66-AS and interfacial proton channels between grafted imidazole groups on Zr-MOFs and SPEEK greatly improve the conductivity of the IM-UIO-66-AS/SPEEK hybrid membrane.More importantly,both reconstructed proton channels block the vanadium-ion permeation to realize enhanced ion selectivity according to the size sieving and Donnan exclusion effects,respectively.Moreover,the hybrid membrane exhibits good mechanical property and dimensional stability.Benefiting from such rational design,a VFB loading with the optimized membrane exhibits enhanced voltage efficiency of 79.9%and outstanding energy efficiency of 79.6%at 200 m A cm^(-2),and keeps a notable cycle stability for 300 cycles in the long-term cycling test.Therefore,this study provides inspiration for preparing next-generation PEMs with high ion selectivity and proton conductivity for VFB application.
基金supported by the Zhejiang Provincial Natural Science Foundation of China(No.LY20E020001)Research Initiation Fund Project from Zhejiang Sci-Tech University(No.22212154-Y)the Fundamental Research Funds of Zhejiang Sci-Tech University(No.22212290-Y)。
文摘Construction of proton transport channels in metal-organic frameworks(MOFs)with simple synthesis processes,high proton conductivities and good performance stabilities has been of great interest for proton exchange membrane fuel cell(PEMFC).Herein,we mimic the proton transport behavior of amino acid residues in bacteriorhodopsin,select UiO-66-COOH as the host,glycine and aspartic acid as the functional vip molecules,and then functionalize the MOF framework with amino acids to obtain biomimetic proton transport channels.This strategy endows UiO-66-COOH-Asp a high proton conductivity of 1.19×10^(-2)S/cm at 70℃and 98%RH,excellent cycle stability of performances and performance durability,which can be comparable to the reported MOFs-based proton conductors.Moreover,the proton conduction mechanism in UiO-66-COOH-Asp is elaborated in detail due to its visual structure,which is also one of the advantages of adopting MOFs as research platform,making it possible to optimize the structure-activity relationship of advanced materials.Notably,this strategy has clear objectives and simple synthesis,which has made certain contributions to both theoretical research and future industrial production of proton conductors.
基金Supported by the Top-Level Talents Support Program of Yangzhou University“Lv Yang Jin Feng”Outstanding Doctor of Yangzhou,No.YZLYJFJH2023YXBS169and Natural Science Foundation of Jiangsu Province,No.BK20240907。
文摘This article discusses a study by Li et al,which investigates the role of the microglial voltage-gated proton channel 1(Hv1)in diabetes-related cognitive decline.The authors showed that Hv1 is upregulated in the corpus callosum of diabetic mice and that its knockout improves working memory,reduces microglial production of interleukin-1βand tumour necrosis factor alpha,and decreases apoptosis of oligodendrocyte progenitor cells.Furthermore,electron microscopy revealed that the myelin thickness and the g-ratio were preserved in Hv1 knockout mice,remaining within normal limits.In addition,Hv1 knockdown mitigated interleukin-1βsecretion and suppressed ferroptosis markers(ferritin heavy chain/ferritin light chain,CCAAT/enhancer binding protein homologous protein,glucose-regulated protein 78,etc.)in vitro,suggesting the involvement of an Hv1-reactive oxygen species-glucose-regulated protein 78 axis in diabetic demyelination.We highlight the translational implications of these findings and recommend future studies employing microglia-specific Hv1 deletion models,longitudinal cognitive assessments and preclinical evaluation of pharmacological Hv1 inhibitors.
基金Supported by the National Natural Science Foundation of China,No.82300894.
文摘BACKGROUND Diabetes is associated with increased cognitive decline and dementia due to the loss of myelinated nerve fiber function,which is linked to oligodendrocyte dysfunction.The voltage-gated proton channel 1(Hv1)is important for the cellular proton extrusion machinery.However,its role in regulating diabetesinduced cognitive dysfunction is unclear.AIM To investigate the role of Hv1 in cognitive impairment induced by diabetes and its potential mechanisms,focusing on neuroinflammation,oligodendrocyte apoptosis,and axonal demyelination.METHODS A diabetes model was established by administering a high-fat diet and streptozotocin injections in mice.Hv1 knockout(KO)and wild-type mice were used to evaluate cognitive function via behavioral tests and neuroinflammation using immunofluorescence.Oligodendrocyte apoptosis was assessed with the terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick-end labeling assay, and axonal demyelination wasanalyzed using electron microscopy.RESULTSHv1 expression was significantly increased in the corpus callosum of diabetic mice. Hv1 KO alleviated cognitiveimpairment, reduced oligodendrocyte apoptosis, and decreased the expression of inflammatory factors, includinginterleukin-1 and tumor necrosis factor-α, in diabetic mice. Electron microscopy revealed a reduction in myelinthickness and an increased g-ratio in diabetic mice, which were reversed by Hv1 KO.CONCLUSIONHv1 plays a role in diabetes-induced cognitive dysfunction by modulating neuroinflammation and myelinintegrity. Hv1 KO demonstrates therapeutic potential in mitigating diabetes-related cognitive decline andassociated complications.
文摘The distinctions between locality and non-locality as well as causality and excess correlation may be related to coupling between increments of space-time or to the total space-time within the universe as a unit. The most likely candidates for the latter are the proton and the electron when related by Minkowski’s space-time. When two velocities: light in a vacuum for locality and the “entanglement” velocity based upon parameters that define the universe for non-locality, are considered the two times required to produce identities for the -v<sup>2</sup>t<sup>2</sup> components are frequencies whose energies approximate the neutral hydrogen line (primarily associated with shifts in electron spin direction) and the mass equivalence of a proton. The values for the additional three spatial dimensions required to produce a solution whose square root is not imaginary and greater than zero are within the domains of the surface areas of the human cerebrum. Detailed calculations converge to show that the proportions of energy that represent the electron’s Compton energy and the proton’s mass equivalent may be central to the condition of excess correlation within the cerebral volume. Proton channels within the neuronal cell plasma membranes whose pH-dependent specific currents produce the required magnetic field strengths could be the physical substrates by which excess correlations between brain activities of human subjects separated by non-local distances might occur. If protons are considered as the basic Eddington (number) units of the universe then Mach’s principle that any component of the universe is determined by all of its components may be testable empirically.
基金the National Institutes of Health(Nos.R01NS110949,R01NS088627,R01NS112144,R01NS110825,R21AG064159)to LJW.
文摘After spinal cord injury,microglia as the first responders to the lesion display both beneficial and detrimental characteristics.Activated microglia phagocyte and eliminate cell debris,release cytokines to recruit peripheral immune cells to the injury site.Excessively activated microglia can aggravate the secondary damage by producing extravagant reactive oxygen species and pro-inflammatory cytokines.Recent studies demonstrated that the voltage-gated proton channel Hv1 is selectively expressed in microglia and regulates microglial activation upon injury.In mouse models of spinal cord injury,Hv1 deficiency ameliorates microglia activation,resulting in alleviated production of reactive oxygen species and pro-inflammatory cytokines.The reduced secondary damage subsequently decreases neuronal loss and correlates with improved locomotor recovery.This review provides a brief historical perspective of advances in investigating voltage-gated proton channel Hv1 and home in on microglial Hv1.We discuss recent studies on the roles of Hv1 activation in pathophysiological activities of microglia,such as production of NOX-dependent reactive oxygen species,microglia polarization,and tissue acidosis,particularly in the context of spinal cord injury.Further,we highlight the rationale for targeting Hv1 for the treatment of spinal cord injury and related disorders.
基金the support from the National Key Research and Development Program of China(2021YFB3801301)the National Natural Science Foundation of China(22075076,21908098,and 21908054)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)。
文摘Ion conductive membranes(ICMs)with highly conductive proton selectivity are of significant importance and greatly desired for energy storage devices.However,it is extremely challenging to construct fast proton-selective transport channels in ICMs.Herein,a membrane with highly conductive proton selectivity was fabricated by incorporating porous carbon sieving nanospheres with a hollow structure(HCSNs)in a polymer matrix.Due to the precise ion sieving ability of the microporous carbon shells and the fast proton transport through their accessible internal cavities,this advanced membrane presented a proton conductivity(0.084 S·cm^(-1))superior to those of a commercial Nation 212(N212)membrane(0.033S·cm^(-1))and a pure polymer membrane(0.049 S·cm^(-1)).The corresponding proton selectivity of the membrane(6.68×10^(5) S·min·cm^(-3))was found to be enhanced by about 5.9-fold and 4.3-fold,respectively,compared with those of the N212 membrane(1.13×10^(5) S·min·cm^(-3))and the pure membrane(1.56×10^(5) S·min·cm^(-3)).Low-field nuclear magnetic resonance(LF-NMR)clearly revealed the fast protonselective transport channels enabled by the HCSNs in the polymeric membrane.The proposed membrane exhibited an outstanding energy efficiency(EE)of 84%and long-term stability over 1400 cycles with a0.065%capacity decay per cycle at 120 mA·cm^(-2) in a typical vanadium flow battery(VFB)system.
文摘The feasibility of producing superheavy nuclei in proton evaporation channels was systematically studied within the dinuclear system(DNS)model.Due to the Z=114 proton-shell,one can synthesize Fl isotopes in proton evaporation channels.We only considered the case of evaporating one proton first and then n neutrons in this work,other cases were ignored due to the small cross-section.The production cross sections of unknown isotopes ^(290,291)Fl in ^(38)S+^(255)Es reaction are the highest compared with ^(50)Ti+^(243)Np and ^(54)Cr+^(239)Pa reactions,and the maximum cross sections are 1.1 and 15.1 pb,respectively.^(42)S+^(254)Es is a promising candidate to approach the island of stability as the radioactive beam facilities are upgraded in the future,and the production cross sections of ^(291−294)Fl in that reaction are estimated to be 3.2,6.0,4.0,and 0.1 pb,respectively.
基金supported by grants from the National Key R&D Program of China(2021YFC2301400)the National Natural Science Foundation of China(32070876,82071155,82271023 and 82301052)the Shanxi Provincial Science Fund for Distinguished Young Scholars program(202103021221001 and 202303021223007).
文摘The cGAS-STING pathway plays a crucial role in the innate immune system by detecting mislocalized double-stranded DNA(dsDNA)in the cytoplasm and triggering downstream signal transduction.Understanding the mechanisms by which cGAS and STING operate is vital for gaining insights into the biology of this pathway.This review provides a detailed examination of the structural features of cGAS and STING proteins,with a particular emphasis on their activation and inhibition mechanisms.We also discuss the novel discovery of STING functioning as an ion channel.Furthermore,we offer an overview of key agonists and antagonists of cGAS and STING,shedding light on their mechanisms of action.Deciphering the molecular intricacies of the cGAS-STING pathway holds significant promise for the development of targeted therapies aimed at maintaining immune homeostasis within both innate and adaptive immunity.
基金We thank Matthew Call for insightful discussion and critical reading of the manuscript.This work was supported by the NIH grant AI054520(to JJC).
文摘The M2 proteins of influenza A and B virus,AM2 and BM2,respectively,are transmembrane proteins that oligomerize in the viral membrane to form proton-selective channels.Proton conductance of the M2 proteins is required for viral replication;it is believed to equilibrate pH across the viral membrane during cell entry and across the trans-Golgi membrane of infected cells during viral maturation.In addition to the role of M2 in proton conductance,recent mutagenesis and structural studies suggest that the cytoplasmic domains of the M2 proteins also play a role in recruiting the matrix proteins to the cell surface during virus budding.As viral ion channels of minimalist architecture,the membrane-embedded channel domain of M2 has been a model system for investigating the mechanism of proton conduction.Moreover,as a proven drug target for the treatment of influenza A infection,M2 has been the subject of intense research for developing new anti-flu therapeutics.AM2 is the target of two anti-influenza A drugs,amantadine and rimantadine,both belonging to the adamantane class of compounds.However,resistance of influenza A to adamantane is now widespread due to mutations in the channel domain of AM2.This review summarizes the structure and function of both AM2 and BM2 channels,the mechanism of drug inhibition and drug resistance of AM2,as well as the development of new M2 inhibitors as potential anti-flu drugs.
