Dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation(HCN)channels alters neuronal excitability.However,the role of HCN channels in status epilepticus is not fully understood.In this study,we est...Dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation(HCN)channels alters neuronal excitability.However,the role of HCN channels in status epilepticus is not fully understood.In this study,we established rat models of pentylenetetrazole-induced status epilepticus.We performed western blot assays and immunofluorescence staining.Our results showed that HCN1 channel protein expression,particularly HCN1 surface protein,was significantly decreased in the hippocampal CA1 region,whereas the expression of HCN2 channel protein was unchanged.Moreover,metabolic glutamate receptor 1(mGluR1)protein expression was increased after status epilepticus.The mGluR1 agonist(RS)-3,5-dihydroxyphenylglycine injected intracerebroventricularly increased the sensitivity and severity of pentylenetetrazole-induced status epilepticus,whereas application of the mGluR1 antagonist(+)-2-methyl-4-carboxyphenylglycine(LY367385)alleviated the severity of pentylenetetrazole-induced status epilepticus.The results from double immunofluorescence labeling revealed that mGluR1 and HCN1 were co-localized in the CA1 region.Subsequently,a protein kinase A inhibitor(H89)administered intraperitoneally successfully reversed HCN1 channel inhibition,thereby suppressing the severity and prolonging the latency of pentylenetetrazole-induced status epilepticus.Furthermore,H89 reduced the level of mGluR1,downregulated cyclic adenosine monophosphate(cAMP)/protein kinase A expression,significantly increased tetratricopeptide repeat-containing Rab8b-interacting protein(TRIP8b)(1a-4)expression,and restored TRIP8b(1b-2)levels.TRIP8b(1a-4)and TRIP8b(1b-2)are subunits of Rab8b interacting protein that regulate HCN1 surface protein.展开更多
超极化激活的环核苷酸（hypepolizion—ived yli nuleoide，HN）通道是一个非选择性离子通道家族，普遍存在于心脏和神经系统中。HN通道家族由于其超极化激活的特性在神经系统中发挥着独特的功能。研究表明HN通道在突触信号的传递和整...超极化激活的环核苷酸（hypepolizion—ived yli nuleoide，HN）通道是一个非选择性离子通道家族，普遍存在于心脏和神经系统中。HN通道家族由于其超极化激活的特性在神经系统中发挥着独特的功能。研究表明HN通道在突触信号的传递和整合中发挥着重要的作用。随着研究的不断深入，越来越多的证据表明敲除HNl的小鼠的运动学习能力受到损害，但空间学习能力反而增强。其机制可能是由于小脑蒲肯野细胞的HNl的缺失，也可能是海马突触环路中某个传导通路或某个神经节点中HNl的缺乏。展开更多
基金supported by the National Natural Science Foundation of China,No.81760242(to MGM).
文摘Dysregulation of hyperpolarization-activated cyclic nucleotide-gated cation(HCN)channels alters neuronal excitability.However,the role of HCN channels in status epilepticus is not fully understood.In this study,we established rat models of pentylenetetrazole-induced status epilepticus.We performed western blot assays and immunofluorescence staining.Our results showed that HCN1 channel protein expression,particularly HCN1 surface protein,was significantly decreased in the hippocampal CA1 region,whereas the expression of HCN2 channel protein was unchanged.Moreover,metabolic glutamate receptor 1(mGluR1)protein expression was increased after status epilepticus.The mGluR1 agonist(RS)-3,5-dihydroxyphenylglycine injected intracerebroventricularly increased the sensitivity and severity of pentylenetetrazole-induced status epilepticus,whereas application of the mGluR1 antagonist(+)-2-methyl-4-carboxyphenylglycine(LY367385)alleviated the severity of pentylenetetrazole-induced status epilepticus.The results from double immunofluorescence labeling revealed that mGluR1 and HCN1 were co-localized in the CA1 region.Subsequently,a protein kinase A inhibitor(H89)administered intraperitoneally successfully reversed HCN1 channel inhibition,thereby suppressing the severity and prolonging the latency of pentylenetetrazole-induced status epilepticus.Furthermore,H89 reduced the level of mGluR1,downregulated cyclic adenosine monophosphate(cAMP)/protein kinase A expression,significantly increased tetratricopeptide repeat-containing Rab8b-interacting protein(TRIP8b)(1a-4)expression,and restored TRIP8b(1b-2)levels.TRIP8b(1a-4)and TRIP8b(1b-2)are subunits of Rab8b interacting protein that regulate HCN1 surface protein.
文摘超极化激活的环核苷酸（hypepolizion—ived yli nuleoide，HN）通道是一个非选择性离子通道家族，普遍存在于心脏和神经系统中。HN通道家族由于其超极化激活的特性在神经系统中发挥着独特的功能。研究表明HN通道在突触信号的传递和整合中发挥着重要的作用。随着研究的不断深入，越来越多的证据表明敲除HNl的小鼠的运动学习能力受到损害，但空间学习能力反而增强。其机制可能是由于小脑蒲肯野细胞的HNl的缺失，也可能是海马突触环路中某个传导通路或某个神经节点中HNl的缺乏。
