超极化激活环核苷酸门控通道在颞叶癫痫的研究新进展_Journal of Epilepsy

Authors：

黎银潮 ¹ , 秦家明 ² , 林婉蓉 ¹ , 陈傲寒 ¹ , 赵怡然 ¹ ,  周列民 ¹

1. ;
2. ;

Corresponding author：

周列民, Email: lmzhou56@163.com

Keywords：

超极化激活环核苷酸门控通道; 伴海马硬化性内侧颞叶癫痫; 研究进展

DOI：

10.7507/2096-0247.20200005

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超极化激活环核苷酸门控通道（Hyperpolarizationactivated cyclic nucleotide gatedchannel，HCN）属于电压门控型离子通道，迄今为止发现有四个亚型：HCN1～HCN4。HCN 通道的激活依赖于膜的超级化，在膜电位低于静息电位时，HCN 通道被激活，产生局部紧张性电流，导致持续的钠内流，使细胞膜发生去极化。该通道分布在人体的分布并不一致，主要在神经系统和心脏中表达。目前研究表明，HCN 通道既参与所在组织的正常生理功能，如睡眠和觉醒、学习和记忆、视觉和疼痛感知、神经元起搏、树突整合等，也与多种中枢神经系统疾病及所在组织的病理状态密切相关，如神经病理性疼痛、学习记忆障碍、药物成瘾和颞叶癫痫，特别是在伴海马硬化性内侧颞叶癫痫中。癫痫作为神经系统最常见的神经疾病之一，癫痫因其病因错综复杂，病理改变亦多样性，至今尚未能完全了解其全部发病机制。目前有大量的文献报道 HCN 与癫痫，特别是颞叶癫痫的发生发展有密切关系。因此本文就 HCN 通道的结构特征、分布、功能、调控及其在颞叶癫痫发生过程中的新研究进展进行综述。

Citation： 黎银潮, 秦家明, 林婉蓉, 陈傲寒, 赵怡然, 周列民. 超极化激活环核苷酸门控通道在颞叶癫痫的研究新进展. Journal of Epilepsy, 2020, 6(1): 19-25. doi: 10.7507/2096-0247.20200005 Copy

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9.	Macri V, Angoli D, Accili EA. Architecture of the HCN selectivity filter and control of cation permeation. Sci Rep, 2012, 2: 894.
10.	Akimoto M, VanSchouwen B, Melacini G. The structure of the apo cAMP-binding domain of HCN4-a stepping stone toward understanding the cAMP-dependent modulation of the hyperpolarization-activated cyclic-nucleotide-gated ion channels. FEBS J, 2018, 285(12): 2182-2192.
11.	Lee CH, MacKinnon R. Structures of the human HCN1 hyperpolarization-activated channel. Cell, 2017, 168(1-2): 111.
12.	Liu C, Xie C, Grant K, et al. Patch-clamp fluorometry-based channel counting to determine HCN channel conductance. J Gen Physiol, 2016, 148(1): 65-76.
13.	Brennan GP, Baram TZ, Poolos NP. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in epilepsy. Cold Spring Harb Perspect Med, 2016, 6(3): a022384.
14.	Notomi T, Shigemoto R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol, 2004, 471(3): 241-276.
15.	Chan CS, Glajch KE, Gertler TS, et al. HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci, 2011, 14(1): 85-92.
16.	Poller WC, Bernard R, Derst C, et al. Lateral habenular neurons projecting to reward-processing monoaminergic nuclei express hyperpolarization-activated cyclic nucleotid-gated cation channels. Neuroscience, 2011, 193: 205-216.
17.	Kouranova EV, Strassle BW, Ring RH, et al. Hyperpolarization-activated cyclic nucleotide-gated channel mRNA and protein expression in large versus small diameter dorsal root ganglion neurons: correlation with hyperpolarization-activated current gating. Neuroscience, 2008, 153(4): 1008-1019.
18.	Powell KL, Jones NC, Kennard JT, et al. HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models. Epilepsia, 2014, 55(4): 609-620.
19.	Seo H, Seol MJ, Lee K. Differential expression of hyperpolarization-activated cyclic nucleotide-gated channel subunits during hippocampal development in the mouse. Mol Brain, 2015, 8: 13.
20.	Boychuk JA, Farrell JS, Palmer LA, et al. HCN channels segregate stimulation-evoked movement responses in neocortex and allow for coordinated forelimb movements in rodents. J Physiol, 2017, 595(1): 247-263.
21.	Weng XC, Liu SJ. Role of HCN channels in the nervous system: membrane excitability and various modulations. Chinese Journal of Applie Physiology, 2014, 30(6): 506-510.
22.	Weerasinghe D, Menon P, Vucic S. Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds. J Neurophysiol, 2017, 118(6): 3044-3050.
23.	Kase D, Imoto K. The role of HCN channels on membrane excitability in the nervous system. J Signal Transduct, 2012, 2012: 619747.
24.	Nolan MF, Malleret G, Lee KH, et al. The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell, 2003, 115(5): 551-564.
25.	Ko KW, Rasband MN, Meseguer V, et al. Serotonin modulates spike probability in the axon initial segment through HCN channels. Nat Neurosci, 2016, 19(6): 826-834.
26.	Hawkins VE, Hawryluk JM, Takakura AC, et al. HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity. J Neurophysiol, 2015, 113(4): 1195-1205.
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28.	Cho YS, Kim YS, Moozhayil SJ, et al. The expression of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and HCN2 in the rat trigeminal ganglion, sensory root, and dental pulp. Neuroscience, 2015, 291: 15-25.
29.	Luo P, Lu Y, Li C, et al. Long-lasting spatial learning and memory impairments caused by chronic cerebral hypoperfusion associate with a dynamic change of HCN1/HCN2 expression in hippocampal CA1 region. Neurobiol Learn Mem, 2015, 123: 72-83.
30.	Williams AD, Jung S, Poolos NP. Protein kinase C bidirectionally modulates Ih and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression in hippocampal pyramidal neurons. J Physiol, 2015, 593(13): 2779-2792.
31.	Hammelmann V, Stieglitz MS, Hulle H, et al. Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures. JCI Insight, 2019, 4(9): 126418.
32.	DeBerg HA, Brzovic PS, Flynn GE, et al. Structure and energetics of allosteric regulation of HCN2 ion channels by cyclic nucleotides. J Biol Chem, 2016, 291(1): 371-381.
33.	Kusch J, Biskup C, Thon S, et al. Interdependence of receptor activation and ligand binding in HCN2 pacemaker channels. Neuron, 2010, 67(1): 75-85.
34.	Ying SW, Tibbs GR, Picollo A, et al. PIP2-mediated HCN3 channel gating is crucial for rhythmic burst firing in thalamic intergeniculate leaflet neurons. J Neurosci, 2011, 31(28): 10412-10423.
35.	Grzelka K, Kurowski P, Gawlak M, et al. Noradrenaline modulates the membrane potential and holding current of medial prefrontal cortex pyramidal neurons via beta1-Adrenergic receptors and HCN channels. Front Cell Neurosci, 2017, 11: 341.
36.	Li CH, Zhang Q, Teng B, et al. Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531. Am J Physiol Cell Physiol, 2008, 294(1): 355-362.
37.	Jung S, Bullis JB, Lau IH, Jones TD, Warner LN, Poolos NP. Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling. J Neurosci, 2010, 30(19): 6678-88.
38.	Poolos NP, Bullis JB, Roth MK. Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase. J Neurosci, 2006, 26(30): 7995-8003.
39.	Shin M, Chetkovich DM. Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons. J Biol Chem, 2007, 282(45): 33168-33180.
40.	Parker AR, Welch MA, Forster LA, et al. SUMOylation of the hyperpolarization-activated cyclic nucleotide-gated channel 2 increases surface expression and the maximal conductance of the hyperpolarization-activated current. Front Mol Neurosci, 2016, 9: 168.
41.	Noam Y, Ehrengruber MU, Koh A, et al. Filamin A promotes dynamin-dependent internalization of hyperpolarization-activated cyclic nucleotide-gated type 1 (HCN1) channels and restricts Ih in hippocampal neurons. J Biol Chem, 2014, 289(9): 5889-5903.
42.	Rafizadeh S, Zhang Z, Woltz RL, et al. Functional interaction with filamin A and intracellular Ca2+enhance the surface membrane expression of a small-conductance Ca2+-activated K+(SK2) channel. Proc Natl Acad Sci U S A, 2014, 111(27): 9989-9994.
43.	Santoro B, Piskorowski RA, Pian P, et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron, 2009, 62(6): 802-813.
44.	Bankston JR, DeBerg HA, Stoll S, et al. Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b. J Biol Chem, 2017, 292(43): 17794-17803.
45.	Piskorowski R, Santoro B, Siegelbaum SA. TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron, 2011, 70(3): 495-509.
46.	Barbuti A, Scavone A, Mazzocchi N, et al. A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins. J Mol Cell Cardiol, 2012, 53(2): 187-195.
47.	Michels G, Er F, Khan IF, et al. K+channel regulator KCR1 suppresses heart rhythm by modulating the pacemaker current If. PLoS One, 2008, 3(1): e1511.
48.	Wilkars W, Wollberg J, Mohr E, et al. Nedd4-2 regulates surface expression and may affect N-glycosylation of hyperpolarization-activated cyclic nucleotide-gated (HCN)-1 channels. FASEB J, 2014, 28(5): 2177-2190.
49.	Mu P, Huang YH. Cholinergic system in sleep regulation of emotion and motivation. Pharmacol Res, 2019, 143: 113-118.
50.	Zhao Z, Zhang K, Liu X, et al. Involvement of HCN channel in muscarinic inhibitory action on tonic firing of dorsolateral striatal cholinergic interneurons. Front Cell Neurosci, 2016, 10: 71.
51.	Dai Y, Jordan LM. Multiple effects of serotonin and acetylcholine on hyperpolarization-activated inward current in locomotor activity-related neurons in Cfos-EGFP mice. J Neurophysiol, 2010, 104(1): 366-381.
52.	Carr DB, Andrews GD, Glen WB, et al. alpha2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584(Pt 2): 437-450.
53.	Gamo NJ, Lur G, Higley MJ, et al. Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels. Biol Psychiatry, 2015, 78(12): 860-870.
54.	Paspalas CD, Wang M, Arnsten AF. Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia. Cereb Cortex, 2013, 23(7): 1643-54.
55.	Liu Z, Bunney EB, Appel SB, et al. Serotonin reduces the hyperpolarization-activated current (Ih) in ventral tegmental area dopamine neurons: involvement of 5-HT2 receptors and protein kinase C. J Neurophysiol, 2003, 90(5): 3201-3212.
56.	Balakrishnan S, Mironov SL. CA1 Neurons acquire rett syndrome phenotype after brief activation of glutamatergic receptors: specific role of mGluR1/5. Front Cell Neurosci, 2018, 12: 363.
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1. Beghi E, Giussani G. Aging and the epidemiology of epilepsy. Neuroepidemiology, 2018, 51(3-4): 216-223.
2. Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol, 2017, 8: 301.
3. Thom M. Review: Hippocampal sclerosis in epilepsy: a neuropathology review. Neuropathol Appl Neurobiol, 2014, 40(5): 520-543.
4. Cendes F, Sakamoto AC, Spreafico R, et al. Epilepsies associated with hippocampal sclerosis. Acta Neuropathol, 2014, 128(1): 21-37.
5. Lerche H, Shah M, Beck H, et al. Ion channels in genetic and acquired forms of epilepsy. J Physiol, 2013, 591(4): 753-764.
6. Nava C, Dalle C, Rastetter A, et al. De novo mutations in HCN1 cause early infantile epileptic encephalopathy. Nat Genet, 2014, 46(6): 640-645.
7. Marini C, Porro A, Rastetter A, et al. HCN1 mutation spectrum: from neonatal epileptic encephalopathy to benign generalized epilepsy and beyond. Brain, 2018, 141(11): 3160-3178.
8. He C, Chen F, Li B, et al. Neurophysiology of HCN channels: from cellular functions to multiple regulations. Prog Neurobiol, 2014, 112: 1-23.
9. Macri V, Angoli D, Accili EA. Architecture of the HCN selectivity filter and control of cation permeation. Sci Rep, 2012, 2: 894.
10. Akimoto M, VanSchouwen B, Melacini G. The structure of the apo cAMP-binding domain of HCN4-a stepping stone toward understanding the cAMP-dependent modulation of the hyperpolarization-activated cyclic-nucleotide-gated ion channels. FEBS J, 2018, 285(12): 2182-2192.
11. Lee CH, MacKinnon R. Structures of the human HCN1 hyperpolarization-activated channel. Cell, 2017, 168(1-2): 111.
12. Liu C, Xie C, Grant K, et al. Patch-clamp fluorometry-based channel counting to determine HCN channel conductance. J Gen Physiol, 2016, 148(1): 65-76.
13. Brennan GP, Baram TZ, Poolos NP. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in epilepsy. Cold Spring Harb Perspect Med, 2016, 6(3): a022384.
14. Notomi T, Shigemoto R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol, 2004, 471(3): 241-276.
15. Chan CS, Glajch KE, Gertler TS, et al. HCN channelopathy in external globus pallidus neurons in models of Parkinson's disease. Nat Neurosci, 2011, 14(1): 85-92.
16. Poller WC, Bernard R, Derst C, et al. Lateral habenular neurons projecting to reward-processing monoaminergic nuclei express hyperpolarization-activated cyclic nucleotid-gated cation channels. Neuroscience, 2011, 193: 205-216.
17. Kouranova EV, Strassle BW, Ring RH, et al. Hyperpolarization-activated cyclic nucleotide-gated channel mRNA and protein expression in large versus small diameter dorsal root ganglion neurons: correlation with hyperpolarization-activated current gating. Neuroscience, 2008, 153(4): 1008-1019.
18. Powell KL, Jones NC, Kennard JT, et al. HCN channelopathy and cardiac electrophysiologic dysfunction in genetic and acquired rat epilepsy models. Epilepsia, 2014, 55(4): 609-620.
19. Seo H, Seol MJ, Lee K. Differential expression of hyperpolarization-activated cyclic nucleotide-gated channel subunits during hippocampal development in the mouse. Mol Brain, 2015, 8: 13.
20. Boychuk JA, Farrell JS, Palmer LA, et al. HCN channels segregate stimulation-evoked movement responses in neocortex and allow for coordinated forelimb movements in rodents. J Physiol, 2017, 595(1): 247-263.
21. Weng XC, Liu SJ. Role of HCN channels in the nervous system: membrane excitability and various modulations. Chinese Journal of Applie Physiology, 2014, 30(6): 506-510.
22. Weerasinghe D, Menon P, Vucic S. Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds. J Neurophysiol, 2017, 118(6): 3044-3050.
23. Kase D, Imoto K. The role of HCN channels on membrane excitability in the nervous system. J Signal Transduct, 2012, 2012: 619747.
24. Nolan MF, Malleret G, Lee KH, et al. The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell, 2003, 115(5): 551-564.
25. Ko KW, Rasband MN, Meseguer V, et al. Serotonin modulates spike probability in the axon initial segment through HCN channels. Nat Neurosci, 2016, 19(6): 826-834.
26. Hawkins VE, Hawryluk JM, Takakura AC, et al. HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity. J Neurophysiol, 2015, 113(4): 1195-1205.
27. Sartiani L, Mannaioni G, Masi A, et al. The hyperpolarization-activated cyclic nucleotide-gated channels: from biophysics to pharmacology of a unique family of ion channels. Pharmacol Rev, 2017, 69(4): 354-395.
28. Cho YS, Kim YS, Moozhayil SJ, et al. The expression of hyperpolarization-activated cyclic nucleotide-gated channel 1 (HCN1) and HCN2 in the rat trigeminal ganglion, sensory root, and dental pulp. Neuroscience, 2015, 291: 15-25.
29. Luo P, Lu Y, Li C, et al. Long-lasting spatial learning and memory impairments caused by chronic cerebral hypoperfusion associate with a dynamic change of HCN1/HCN2 expression in hippocampal CA1 region. Neurobiol Learn Mem, 2015, 123: 72-83.
30. Williams AD, Jung S, Poolos NP. Protein kinase C bidirectionally modulates Ih and hyperpolarization-activated cyclic nucleotide-gated (HCN) channel surface expression in hippocampal pyramidal neurons. J Physiol, 2015, 593(13): 2779-2792.
31. Hammelmann V, Stieglitz MS, Hulle H, et al. Abolishing cAMP sensitivity in HCN2 pacemaker channels induces generalized seizures. JCI Insight, 2019, 4(9): 126418.
32. DeBerg HA, Brzovic PS, Flynn GE, et al. Structure and energetics of allosteric regulation of HCN2 ion channels by cyclic nucleotides. J Biol Chem, 2016, 291(1): 371-381.
33. Kusch J, Biskup C, Thon S, et al. Interdependence of receptor activation and ligand binding in HCN2 pacemaker channels. Neuron, 2010, 67(1): 75-85.
34. Ying SW, Tibbs GR, Picollo A, et al. PIP2-mediated HCN3 channel gating is crucial for rhythmic burst firing in thalamic intergeniculate leaflet neurons. J Neurosci, 2011, 31(28): 10412-10423.
35. Grzelka K, Kurowski P, Gawlak M, et al. Noradrenaline modulates the membrane potential and holding current of medial prefrontal cortex pyramidal neurons via beta1-Adrenergic receptors and HCN channels. Front Cell Neurosci, 2017, 11: 341.
36. Li CH, Zhang Q, Teng B, et al. Src tyrosine kinase alters gating of hyperpolarization-activated HCN4 pacemaker channel through Tyr531. Am J Physiol Cell Physiol, 2008, 294(1): 355-362.
37. Jung S, Bullis JB, Lau IH, Jones TD, Warner LN, Poolos NP. Downregulation of dendritic HCN channel gating in epilepsy is mediated by altered phosphorylation signaling. J Neurosci, 2010, 30(19): 6678-88.
38. Poolos NP, Bullis JB, Roth MK. Modulation of h-channels in hippocampal pyramidal neurons by p38 mitogen-activated protein kinase. J Neurosci, 2006, 26(30): 7995-8003.
39. Shin M, Chetkovich DM. Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons. J Biol Chem, 2007, 282(45): 33168-33180.
40. Parker AR, Welch MA, Forster LA, et al. SUMOylation of the hyperpolarization-activated cyclic nucleotide-gated channel 2 increases surface expression and the maximal conductance of the hyperpolarization-activated current. Front Mol Neurosci, 2016, 9: 168.
41. Noam Y, Ehrengruber MU, Koh A, et al. Filamin A promotes dynamin-dependent internalization of hyperpolarization-activated cyclic nucleotide-gated type 1 (HCN1) channels and restricts Ih in hippocampal neurons. J Biol Chem, 2014, 289(9): 5889-5903.
42. Rafizadeh S, Zhang Z, Woltz RL, et al. Functional interaction with filamin A and intracellular Ca2+enhance the surface membrane expression of a small-conductance Ca2+-activated K+(SK2) channel. Proc Natl Acad Sci U S A, 2014, 111(27): 9989-9994.
43. Santoro B, Piskorowski RA, Pian P, et al. TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron, 2009, 62(6): 802-813.
44. Bankston JR, DeBerg HA, Stoll S, et al. Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b. J Biol Chem, 2017, 292(43): 17794-17803.
45. Piskorowski R, Santoro B, Siegelbaum SA. TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron, 2011, 70(3): 495-509.
46. Barbuti A, Scavone A, Mazzocchi N, et al. A caveolin-binding domain in the HCN4 channels mediates functional interaction with caveolin proteins. J Mol Cell Cardiol, 2012, 53(2): 187-195.
47. Michels G, Er F, Khan IF, et al. K+channel regulator KCR1 suppresses heart rhythm by modulating the pacemaker current If. PLoS One, 2008, 3(1): e1511.
48. Wilkars W, Wollberg J, Mohr E, et al. Nedd4-2 regulates surface expression and may affect N-glycosylation of hyperpolarization-activated cyclic nucleotide-gated (HCN)-1 channels. FASEB J, 2014, 28(5): 2177-2190.
49. Mu P, Huang YH. Cholinergic system in sleep regulation of emotion and motivation. Pharmacol Res, 2019, 143: 113-118.
50. Zhao Z, Zhang K, Liu X, et al. Involvement of HCN channel in muscarinic inhibitory action on tonic firing of dorsolateral striatal cholinergic interneurons. Front Cell Neurosci, 2016, 10: 71.
51. Dai Y, Jordan LM. Multiple effects of serotonin and acetylcholine on hyperpolarization-activated inward current in locomotor activity-related neurons in Cfos-EGFP mice. J Neurophysiol, 2010, 104(1): 366-381.
52. Carr DB, Andrews GD, Glen WB, et al. alpha2-Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents. J Physiol, 2007, 584(Pt 2): 437-450.
53. Gamo NJ, Lur G, Higley MJ, et al. Stress impairs prefrontal cortical function via D1 dopamine receptor interactions with hyperpolarization-activated cyclic nucleotide-gated channels. Biol Psychiatry, 2015, 78(12): 860-870.
54. Paspalas CD, Wang M, Arnsten AF. Constellation of HCN channels and cAMP regulating proteins in dendritic spines of the primate prefrontal cortex: potential substrate for working memory deficits in schizophrenia. Cereb Cortex, 2013, 23(7): 1643-54.
55. Liu Z, Bunney EB, Appel SB, et al. Serotonin reduces the hyperpolarization-activated current (Ih) in ventral tegmental area dopamine neurons: involvement of 5-HT2 receptors and protein kinase C. J Neurophysiol, 2003, 90(5): 3201-3212.
56. Balakrishnan S, Mironov SL. CA1 Neurons acquire rett syndrome phenotype after brief activation of glutamatergic receptors: specific role of mGluR1/5. Front Cell Neurosci, 2018, 12: 363.
57. Bender RA, Baram TZ. Hyperpolarization activated cyclic-nucleotide gated (HCN) channels in developing neuronal networks. Prog Neurobiol, 2008, 86(3): 129-140.
58. DiFrancesco JC, DiFrancesco D. Dysfunctional HCN ion channels in neurological diseases. Front Cell Neurosci, 2015, 6: 174.
59. Huang Z, Walker MC, Shah MM. Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. J Neurosci, 2009, 29(35): 10979-10988.
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超极化激活环核苷酸门控通道在颞叶癫痫的研究新进展

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