Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may de...Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.展开更多
Voltage-gated sodium channels play an important role in the generation and propagation of action potentials in excitable cells. They are composed of a pore-forming α subunit and auxiliary β subunits. To date, nine s...Voltage-gated sodium channels play an important role in the generation and propagation of action potentials in excitable cells. They are composed of a pore-forming α subunit and auxiliary β subunits. To date, nine subtypes of the α subunit, designated Nav1.1 to Nav1.9, have been shown to form functional sodium channels. In addition, four different mammalian subunits (β1-β4) isoforms have been cloned from the nervous system. The β subunits are structurally homologous and form single transmembrane glycoproteins with short intracellular loops and immunoglobulin-like extracellular segments. The association of the various α subtypes with different combinations of auxiliary β subunits creates the possibility of additional molecular and functional complexity for neuronal sodium channels.展开更多
Objective In this study, the pharmacological kinetics of Buthus martensi Karsch (BmK) AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods...Objective In this study, the pharmacological kinetics of Buthus martensi Karsch (BmK) AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations (10, 100, and 500 nmol/L). Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.展开更多
基金supported by the Natural Science Foundation of Guangdong Province,Nos.2019A1515010649(to WC),2022A1515012044(to JS)the China Postdoctoral Science Foundation,No.2018M633091(to JS).
文摘Transforming growth factor-beta 1(TGF-β1)has been extensively studied for its pleiotropic effects on central nervous system diseases.The neuroprotective or neurotoxic effects of TGF-β1 in specific brain areas may depend on the pathological process and cell types involved.Voltage-gated sodium channels(VGSCs)are essential ion channels for the generation of action potentials in neurons,and are involved in various neuroexcitation-related diseases.However,the effects of TGF-β1 on the functional properties of VGSCs and firing properties in cortical neurons remain unclear.In this study,we investigated the effects of TGF-β1 on VGSC function and firing properties in primary cortical neurons from mice.We found that TGF-β1 increased VGSC current density in a dose-and time-dependent manner,which was attributable to the upregulation of Nav1.3 expression.Increased VGSC current density and Nav1.3 expression were significantly abolished by preincubation with inhibitors of mitogen-activated protein kinase kinase(PD98059),p38 mitogen-activated protein kinase(SB203580),and Jun NH2-terminal kinase 1/2 inhibitor(SP600125).Interestingly,TGF-β1 significantly increased the firing threshold of action potentials but did not change their firing rate in cortical neurons.These findings suggest that TGF-β1 can increase Nav1.3 expression through activation of the ERK1/2-JNK-MAPK pathway,which leads to a decrease in the firing threshold of action potentials in cortical neurons under pathological conditions.Thus,this contributes to the occurrence and progression of neuroexcitatory-related diseases of the central nervous system.
基金grants from the National Natural Science Foundation of China(No.30300330)Qimingxing program of Shanghai(No.05QMX1431)
文摘Voltage-gated sodium channels play an important role in the generation and propagation of action potentials in excitable cells. They are composed of a pore-forming α subunit and auxiliary β subunits. To date, nine subtypes of the α subunit, designated Nav1.1 to Nav1.9, have been shown to form functional sodium channels. In addition, four different mammalian subunits (β1-β4) isoforms have been cloned from the nervous system. The β subunits are structurally homologous and form single transmembrane glycoproteins with short intracellular loops and immunoglobulin-like extracellular segments. The association of the various α subtypes with different combinations of auxiliary β subunits creates the possibility of additional molecular and functional complexity for neuronal sodium channels.
基金supported by grants from the National Basic Research Development Program of China (2010CB529806)the National Natural Science Foundation of China (31171064)+1 种基金the Key Research Program of Science and Technology Commissions of Shanghai Municipality (11JC1404300)the Leading Academic Discipline Project of Shanghai Municipal Education Commission (J50108)
文摘Objective In this study, the pharmacological kinetics of Buthus martensi Karsch (BmK) AS, a specific modulator of voltage-gated sodium channel site 4, was investigated on Nav1.3 expressed in Xenopus oocytes. Methods Two-electrode voltage clamp was used to record the whole-cell sodium current. Results The peak currents of Nav1.3 were depressed by BmK AS over a wide range of concentrations (10, 100, and 500 nmol/L). Most remarkably, BmK AS at 100 nmol/L hyperpolarized the voltage-dependence and increased the voltage-sensitivity of steady-state activation/inactivation. In addition, BmK AS was capable of hyperpolarizing not only the fast inactivation but also the slow inactivation, with a greater preference for the latter. Moreover, BmK AS accelerated the time constant and increased the ratio of recovery in Nav1.3 at all concentrations. Conclusion This study provides direct evidence that BmK AS facilitates steady-state activation and inhibits slow inactivation by stabilizing both the closed and open states of the Nav1.3 channel, which might result from an integrative binding to two receptor sites on the voltage-gated sodium channels. These results may shed light on therapeutics against Nav1.3-targeted pathology.