Login Register Cart 0
Generic placeholder image

Current Neuropharmacology

Editor-in-Chief

ISSN (Print): 1570-159X
ISSN (Online): 1875-6190

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Review Article

The Impact of Altered HCN1 Expression on Brain Function and Its Relationship with Epileptogenesis

Author(s): Ke Zhao, Yinchao Li, Xiaofeng Yang* and Liemin Zhou*

Volume 21, Issue 10, 2023

Published on: 14 February, 2023

Page: [2070 - 2078] Pages: 9

DOI: 10.2174/1570159X21666230214110333

Price: $65

Abstract

Hyperpolarization-activated cyclic nucleotide-gated cation channel 1 (HCN1) is predominantly expressed in neurons from the neocortex and hippocampus, two important regions related to epilepsy. Both animal models for epilepsy and epileptic patients show decreased HCN1 expression and HCN1-mediated Ih current. It has been shown in neuroelectrophysiological experiments that a decreased Ih current can increase neuronal excitability. However, some studies have shown that blocking the Ih current in vivo can exert antiepileptic effects. This paradox raises an important question regarding the causal relationship between HCN1 alteration and epileptogenesis, which to date has not been elucidated. In this review, we summarize the literature related to HCN1 and epilepsy, aiming to find a possible explanation for this paradox, and explore the correlation between HCN1 and the mechanism of epileptogenesis. We analyze the alterations in the expression and distribution of HCN1 and the corresponding impact on brain function in epilepsy. In addition, we also discuss the effect of blocking Ih on epilepsy symptoms. Addressing these issues will help to inspire new strategies to explore the relationship between HCN1 and epileptogenesis, and ultimately promote the development of new targets for epilepsy therapy.

« Previous Next »
Graphical Abstract

[1]
Pape, H-C. Queer current and pacemaker: The hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol., 1996, 58(1), 299-327.
[http://dx.doi.org/10.1146/annurev.ph.58.030196.001503] [PMID: 8815797]
[2]
Ludwig, A.; Zong, X.; Jeglitsch, M.; Hofmann, F.; Biel, M. A family of hyperpolarization-activated mammalian cation channels. Nature, 1998, 393(6685), 587-591.
[http://dx.doi.org/10.1038/31255] [PMID: 9634236]
[3]
Robinson, R.B.; Siegelbaum, S.A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol., 2003, 65(1), 453-480.
[http://dx.doi.org/10.1146/annurev.physiol.65.092101.142734] [PMID: 12471170]
[4]
Yanagihara, K.; Irisawa, H. Inward current activated during hyperpolarization in the rabbit sinoatrial node cell. Pflugers Arch., 1980, 385(1), 11-19.
[http://dx.doi.org/10.1007/BF00583909] [PMID: 7191093]
[5]
Santoro, B.; Tibbs, G.R. The HCN gene family: molecular basis of the hyperpolarization-activated pacemaker channels. Ann. N. Y. Acad. Sci., 1999, 868(1 MOLECULAR AND), 741-764.
[http://dx.doi.org/10.1111/j.1749-6632.1999.tb11353.x] [PMID: 10414361]
[6]
Schwartzkroin, P.A. Role of the hippocampus in epilepsy. Hippocampus, 1994, 4(3), 239-242.
[http://dx.doi.org/10.1002/hipo.450040302] [PMID: 7842043]
[7]
Notomi, T.; Shigemoto, R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J. Comp. Neurol., 2004, 471(3), 241-276.
[http://dx.doi.org/10.1002/cne.11039] [PMID: 14991560]
[8]
Brewster, A.L.; Chen, Y.; Bender, R.A.; Yeh, A.; Shigemoto, R.; Baram, T.Z. Quantitative analysis and subcellular distribution of mRNA and protein expression of the hyperpolarization-activated cyclic nucleotide-gated channels throughout development in rat hippocampus. Cereb. Cortex, 2006, 17(3), 702-712.
[http://dx.doi.org/10.1093/cercor/bhk021] [PMID: 16648453]
[9]
Blumcke, I.; Budday, S.; Poduri, A.; Lal, D.; Kobow, K.; Baulac, S. Neocortical development and epilepsy: insights from focal cortical dysplasia and brain tumours. Lancet Neurol., 2021, 20(11), 943-955.
[http://dx.doi.org/10.1016/S1474-4422(21)00265-9] [PMID: 34687638]
[10]
Chen, K.; Aradi, I.; Thon, N.; Mariam Eghbal-Ahmadi, T.Z.B.; Soltesz, I.; Brewster, A.; Brewster, A. Persistantly modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Net. Med., 2001, 7(3), 331-337.
[11]
Brewster, A.; Bender, R.A.; Chen, Y.; Dube, C.; Eghbal-Ahmadi, M.; Baram, T.Z. Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner. J. Neurosci., 2002, 22(11), 4591-4599.
[http://dx.doi.org/10.1523/JNEUROSCI.22-11-04591.2002] [PMID: 12040066]
[12]
Bender, R.A.; Soleymani, S.V.; Brewster, A.L.; Nguyen, S.T.; Beck, H.; Mathern, G.W.; Baram, T.Z. Enhanced expression of a specific hyperpolarization-activated cyclic nucleotide-gated cation channel (HCN) in surviving dentate gyrus granule cells of human and experimental epileptic hippocampus. J. Neurosci., 2003, 23(17), 6826-6836.
[http://dx.doi.org/10.1523/JNEUROSCI.23-17-06826.2003] [PMID: 12890777]
[13]
Shah, M.M.; Anderson, A.E.; Leung, V.; Lin, X.; Johnston, D. Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons. Neuron, 2004, 44(3), 495-508.
[http://dx.doi.org/10.1016/j.neuron.2004.10.011] [PMID: 15504329]
[14]
Jung, S.; Jones, T.D.; Lugo, J.N., Jr; Sheerin, A.H.; Miller, J.W.; D’Ambrosio, R.; Anderson, A.E.; Poolos, N.P. Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy. J. Neurosci., 2007, 27(47), 13012-13021.
[http://dx.doi.org/10.1523/JNEUROSCI.3605-07.2007] [PMID: 18032674]
[15]
Kole, M.H.P.; Bräuer, A.U.; Stuart, G.J. Inherited cortical HCN1 channel loss amplifies dendritic calcium electrogenesis and burst firing in a rat absence epilepsy model. J. Physiol., 2007, 578(2), 507-525.
[http://dx.doi.org/10.1113/jphysiol.2006.122028] [PMID: 17095562]
[16]
Lin, W.; Qin, J.; Ni, G.; Li, Y.; Xie, H.; Yu, J.; Li, H.; Sui, L.; Guo, Q.; Fang, Z.; Zhou, L. Downregulation of hyperpolarization‐activated cyclic nucleotide‐gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE‐HS). Hippocampus, 2020, 30(10), 1112-1126.
[http://dx.doi.org/10.1002/hipo.23219] [PMID: 32543742]
[17]
Shin, M.; Brager, D.; Jaramillo, T.C.; Johnston, D.; Chetkovich, D.M. Mislocalization of h channel subunits underlies h channelopathy in temporal lobe epilepsy. Neurobiol. Dis., 2008, 32(1), 26-36.
[http://dx.doi.org/10.1016/j.nbd.2008.06.013] [PMID: 18657617]
[18]
DiFrancesco, J.C.; Castellotti, B.; Milanesi, R.; Ragona, F.; Freri, E.; Canafoglia, L.; Franceschetti, S.; Ferrarese, C.; Magri, S.; Taroni, F.; Costa, C.; Labate, A.; Gambardella, A.; Solazzi, R.; Binda, A.; Rivolta, I.; Di Gennaro, G.; Casciato, S.; D’Incerti, L.; Barbuti, A.; DiFrancesco, D.; Granata, T.; Gellera, C. HCN ion channels and accessory proteins in epilepsy: genetic analysis of a large cohort of patients and review of the literature. Epilepsy Res., 2019, 153, 49-58.
[http://dx.doi.org/10.1016/j.eplepsyres.2019.04.004] [PMID: 30986657]
[19]
Bonzanni, M.; DiFrancesco, J.C.; Milanesi, R.; Campostrini, G.; Castellotti, B.; Bucchi, A.; Baruscotti, M.; Ferrarese, C.; Franceschetti, S.; Canafoglia, L.; Ragona, F.; Freri, E.; Labate, A.; Gambardella, A.; Costa, C.; Rivolta, I.; Gellera, C.; Granata, T.; Barbuti, A.; DiFrancesco, D. A novel de novo HCN1 loss-of-function mutation in genetic generalized epilepsy causing increased neuronal excitability. Neurobiol. Dis., 2018, 118, 55-63.
[http://dx.doi.org/10.1016/j.nbd.2018.06.012] [PMID: 29936235]
[20]
Merseburg, A.; Kasemir, J.; Buss, E.W.; Leroy, F.; Bock, T.; Porro, A.; Barnett, A.; Tröder, S.E.; Engeland, B.; Stockebrand, M.; Moroni, A.; Siegelbaum, S.A.; Isbrandt, D.; Santoro, B. Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models of HCN1 epileptic encephalopathy. eLife, 2022, 11, e70826.
[http://dx.doi.org/10.7554/eLife.70826] [PMID: 35972069]
[21]
Kessi, M.; Peng, J.; Duan, H.; He, H.; Chen, B.; Xiong, J.; Wang, Y.; Yang, L.; Wang, G.; Kiprotich, K.; Bamgbade, O.A.; He, F.; Yin, F. The contribution of HCN channelopathies in different epileptic syndromes, mechanisms, modulators, and potential treatment targets: A systematic review. Front. Mol. Neurosci., 2022, 15, 807202.
[http://dx.doi.org/10.3389/fnmol.2022.807202] [PMID: 35663267]
[22]
Bleakley, L.E.; McKenzie, C.E.; Soh, M.S.; Forster, I.C.; Pinares-Garcia, P.; Sedo, A.; Kathirvel, A.; Churilov, L.; Jancovski, N.; Maljevic, S.; Berkovic, S.F.; Scheffer, I.E.; Petrou, S.; Santoro, B.; Reid, C.A. Cation leak underlies neuronal excitability in an HCN1 developmental and epileptic encephalopathy. Brain, 2021, 144(7), 2060-2073.
[http://dx.doi.org/10.1093/brain/awab145] [PMID: 33822003]
[23]
Huang, Z.; Walker, M.C.; Shah, M.M. Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. J. Neurosci., 2009, 29(35), 10979-10988.
[http://dx.doi.org/10.1523/JNEUROSCI.1531-09.2009] [PMID: 19726656]
[24]
Łuszczki, J.J.; Prystupa, A.; Andres-Mach, M.; Marzęda, E.; Florek-Łuszczki, M. Ivabradine (a hyperpolarization activated cyclic nucleotide-gated channel blocker) elevates the threshold for maximal electroshock-induced tonic seizures in mice. Pharmacol. Rep., 2013, 65(5), 1407-1414.
[http://dx.doi.org/10.1016/S1734-1140(13)71500-7] [PMID: 24399738]
[25]
Cavalcante, T.M.B.; De Melo, J.M.A.; Lopes, L.B.; Bessa, M.C.; Santos, J.G.; Vasconcelos, L.C.; Vieira Neto, A.E.; Borges, L.T.N.; Fonteles, M.M.F.; Chaves Filho, A.J.M.; Macêdo, D.; Campos, A.R.; Aguiar, C.C.T.; Vasconcelos, S.M.M. Ivabradine possesses anticonvulsant and neuroprotective action in mice. Biomed. Pharmacother., 2019, 109, 2499-2512.
[http://dx.doi.org/10.1016/j.biopha.2018.11.096] [PMID: 30551511]
[26]
Santoro, B.; Shah, M.M. Hyperpolarization-activated cyclic nucleotide-gated channels as drug targets for neurological disorders. Annu. Rev. Pharmacol. Toxicol., 2020, 60(1), 109-131.
[http://dx.doi.org/10.1146/annurev-pharmtox-010919-023356] [PMID: 31914897]
[27]
Hagger-Vaughan, N.; Storm, J.F. Synergy of glutamatergic and cholinergic modulation induces plateau potentials in hippocampal OLM interneurons. Front. Cell. Neurosci., 2019, 13, 508.
[http://dx.doi.org/10.3389/fncel.2019.00508] [PMID: 31780902]
[28]
Nusser, Z. Variability in the subcellular distribution of ion channels increases neuronal diversity. Trends Neurosci., 2009, 32(5), 267-274.
[http://dx.doi.org/10.1016/j.tins.2009.01.003] [PMID: 19299025]
[29]
Lörincz, A.; Notomi, T.; Tamás, G.; Shigemoto, R.; Nusser, Z. Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nat. Neurosci., 2002, 5(11), 1185-1193.
[http://dx.doi.org/10.1038/nn962] [PMID: 12389030]
[30]
Magee, J.C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci., 1998, 18(19), 7613-7624.
[http://dx.doi.org/10.1523/JNEUROSCI.18-19-07613.1998] [PMID: 9742133]
[31]
Poolos, N.P. Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) ion channelopathy in epilepsy. In: Jasper’s Basic Mechanisms of the Epilepsies; Noebels, J.L.; Avoli, M.; Rogawski, M.A.; Olsen, R.W.; Delgado-Escueta, A.V., Eds.; , 2012.
[32]
Magee, J.C. Erratum: Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nat. Neurosci., 1999, 2(9), 848.
[http://dx.doi.org/10.1038/12229] [PMID: 10461231]
[33]
Williams, S.R.; Stuart, G.J. Voltage- and site-dependent control of the somatic impact of dendritic IPSPs. J. Neurosci., 2003, 23(19), 7358-7367.
[http://dx.doi.org/10.1523/JNEUROSCI.23-19-07358.2003] [PMID: 12917370]
[34]
Tsay, D.; Dudman, J.T.; Siegelbaum, S.A. HCN1 channels constrain synaptically evoked Ca2+ spikes in distal dendrites of CA1 pyramidal neurons. Neuron, 2007, 56(6), 1076-1089.
[http://dx.doi.org/10.1016/j.neuron.2007.11.015] [PMID: 18093528]
[35]
George, M.S.; Abbott, L.F.; Siegelbaum, S.A. HCN hyperpolarization-activated cation channels inhibit EPSPs by interactions with M-type K+ channels. Nat. Neurosci., 2009, 12(5), 577-584.
[http://dx.doi.org/10.1038/nn.2307] [PMID: 19363490]
[36]
Brennan, G.P.; Baram, T.Z.; Poolos, N.P. Hyperpolarization-Activated Cyclic Nucleotide-Gated (HCN) Channels in Epilepsy. Cold Spring Harb. Perspect. Med., 2016, 6(3), a022384.
[http://dx.doi.org/10.1101/cshperspect.a022384] [PMID: 26931806]
[37]
Maccaferri, G.; McBain, C.J. Passive propagation of LTD to stratum oriens-alveus inhibitory neurons modulates the temporoammonic input to the hippocampal CA1 region. Neuron, 1995, 15(1), 137-145.
[http://dx.doi.org/10.1016/0896-6273(95)90071-3] [PMID: 7619518]
[38]
Gianmaria, M.; Chris, J.M. The hyperpolarization-activated current (Ih) and its contribution to pacemaker activity in rat CAI hippocampal stratum oriens-alveus interneurones. J. Physiol., 1996, 497(1), 119-130.
[39]
Lupica, C.R.; Bell, J.A.; Hoffman, A.F.; Watson, P.L. Contribution of the hyperpolarization-activated current (I(h)) to membrane potential and GABA release in hippocampal interneurons. J. Neurophysiol., 2001, 86(1), 261-268.
[http://dx.doi.org/10.1152/jn.2001.86.1.261] [PMID: 11431507]
[40]
Aponte, Y.; Lien, C.C.; Reisinger, E.; Jonas, P. Hyperpolarization-activated cation channels in fast-spiking interneurons of rat hippocampus. J. Physiol., 2006, 574(1), 229-243.
[http://dx.doi.org/10.1113/jphysiol.2005.104042] [PMID: 16690716]
[41]
Huang, Z.; Lujan, R.; Kadurin, I.; Uebele, V.N.; Renger, J.J.; Dolphin, A.C.; Shah, M.M. Presynaptic HCN1 channels regulate CaV3.2 activity and neurotransmission at select cortical synapses. Nat. Neurosci., 2011, 14(4), 478-486.
[http://dx.doi.org/10.1038/nn.2757] [PMID: 21358644]
[42]
Huang, Z.; Li, G.; Aguado, C.; Lujan, R.; Shah, M.M. HCN1 channels reduce the rate of exocytosis from a subset of cortical synaptic terminals. Sci. Rep., 2017, 7(1), 40257.
[http://dx.doi.org/10.1038/srep40257] [PMID: 28071723]
[43]
Roth, F.C.; Hu, H. An axon-specific expression of HCN channels catalyzes fast action potential signaling in GABAergic interneurons. Nat. Commun., 2020, 11(1), 2248.
[http://dx.doi.org/10.1038/s41467-020-15791-y] [PMID: 32382046]
[44]
Dyhrfjeld-Johnsen, J.; Morgan, R.J.; Földy, C.; Soltesz, I. Upregulated H-Current in hyperexcitable CA1 dendrites after febrile seizures. Front. Cell. Neurosci., 2008, 2, 2.
[http://dx.doi.org/10.3389/neuro.03.002.2008] [PMID: 18946517]
[45]
Dyhrfjeld-Johnsen, J.; Morgan, R.J.; Soltesz, I. Double trouble? Potential for hyperexcitability following both channelopathic up- and downregulation of Ih in epilepsy. Front. Neurosci., 2009, 3(1), 25-33.
[http://dx.doi.org/10.3389/neuro.01.005.2009] [PMID: 19753094]
[46]
Poolos, N.P. The Yin and Yang of the H-Channel and Its Role in Epilepsy. Epilepsy Curr., 2004, 4(1), 3-6.
[http://dx.doi.org/10.1111/j.1535-7597.2004.04101.x] [PMID: 15346132]
[47]
Lai, H.C.; Jan, L.Y. The distribution and targeting of neuronal voltage-gated ion channels. Nat. Rev. Neurosci., 2006, 7(7), 548-562.
[http://dx.doi.org/10.1038/nrn1938] [PMID: 16791144]
[48]
Honsa, P.; Pivonkova, H.; Harantova, L.; Butenko, O.; Kriska, J.; Dzamba, D.; Rusnakova, V.; Valihrach, L.; Kubista, M.; Anderova, M. Increased expression of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in reactive astrocytes following ischemia. Glia, 2014, 62(12), 2004-2021.
[http://dx.doi.org/10.1002/glia.22721] [PMID: 25042871]
[49]
Vay, S.U.; Flitsch, L.J.; Rabenstein, M.; Monière, H.; Jakovcevski, I.; Andjus, P.; Bijelic, D.; Blaschke, S.; Walter, H.L.; Fink, G.R.; Schroeter, M.; Rueger, M.A. The impact of hyperpolarization-activated cyclic nucleotide-gated (HCN) and voltage-gated potassium KCNQ/Kv7 channels on primary microglia function. J. Neuroinflammation, 2020, 17(1), 100.
[http://dx.doi.org/10.1186/s12974-020-01779-4] [PMID: 32248813]
[50]
Fan, Y.; Fricker, D.; Brager, D.H.; Chen, X.; Lu, H.C.; Chitwood, R.A.; Johnston, D. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih. Nat. Neurosci., 2005, 8(11), 1542-1551.
[http://dx.doi.org/10.1038/nn1568] [PMID: 16234810]
[51]
Noam, Y.; Zha, Q.; Phan, L.; Wu, R.L.; Chetkovich, D.M.; Wadman, W.J.; Baram, T.Z. Trafficking and surface expression of hyperpolarization-activated cyclic nucleotide-gated channels in hippocampal neurons. J. Biol. Chem., 2010, 285(19), 14724-14736.
[http://dx.doi.org/10.1074/jbc.M109.070391] [PMID: 20215108]
[52]
Brager, D.H.; Johnston, D. Plasticity of intrinsic excitability during long-term depression is mediated through mGluR-dependent changes in I(h) in hippocampal CA1 pyramidal neurons. J. Neurosci., 2007, 27(51), 13926-13937.
[http://dx.doi.org/10.1523/JNEUROSCI.3520-07.2007] [PMID: 18094230]
[53]
Richichi, C.; Brewster, A.L.; Bender, R.A.; Simeone, T.A.; Zha, Q.; Yin, H.Z.; Weiss, J.H.; Baram, T.Z. Mechanisms of seizure-induced ‘transcriptional channelopathy’ of hyperpolarization-activated cyclic nucleotide gated (HCN) channels. Neurobiol. Dis., 2008, 29(2), 297-305.
[http://dx.doi.org/10.1016/j.nbd.2007.09.003] [PMID: 17964174]
[54]
Shin, M.; Chetkovich, D.M. Activity-dependent regulation of h channel distribution in hippocampal CA1 pyramidal neurons. J. Biol. Chem., 2007, 282(45), 33168-33180.
[http://dx.doi.org/10.1074/jbc.M703736200] [PMID: 17848552]
[55]
Lewis, A.S.; Schwartz, E.; Savio Chan, C.; Noam, Y.; Shin, M.; Wadman, W.J.; James Surmeier, D.; Baram, T.Z.; Macdonald, R.L.; Chetkovich, D.M. Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. J. Neurosci., 2009, 29(19), 6250-6265.
[http://dx.doi.org/10.1523/JNEUROSCI.0856-09.2009] [PMID: 19439603]
[56]
Lewis, A.S.; Vaidya, S.P.; Blaiss, C.A.; Liu, Z.; Stoub, T.R.; Brager, D.H.; Chen, X.; Bender, R.A.; Estep, C.M.; Popov, A.B.; Kang, C.E.; Van Veldhoven, P.P.; Bayliss, D.A.; Nicholson, D.A.; Powell, C.M.; Johnston, D.; Chetkovich, D.M. Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. J. Neurosci., 2011, 31(20), 7424-7440.
[http://dx.doi.org/10.1523/JNEUROSCI.0936-11.2011] [PMID: 21593326]
[57]
Heuermann, R.J.; Jaramillo, T.C.; Ying, S.W.; Suter, B.A.; Lyman, K.A.; Han, Y.; Lewis, A.S.; Hampton, T.G.; Shepherd, G.M.G.; Goldstein, P.A.; Chetkovich, D.M. Reduction of thalamic and cortical I h by deletion of TRIP8b produces a mouse model of human absence epilepsy. Neurobiol. Dis., 2016, 85, 81-92.
[http://dx.doi.org/10.1016/j.nbd.2015.10.005] [PMID: 26459112]
[58]
Foote, K.M.; Lyman, K.A.; Han, Y.; Michailidis, I.E.; Heuermann, R.J.; Mandikian, D.; Trimmer, J.S.; Swanson, G.T.; Chetkovich, D.M. Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function. J. Biol. Chem., 2019, 294(43), 15743-15758.
[http://dx.doi.org/10.1074/jbc.RA119.010027] [PMID: 31492750]
[59]
McClelland, S.; Flynn, C.; Dubé, C.; Richichi, C.; Zha, Q.; Ghestem, A.; Esclapez, M.; Bernard, C.; Baram, T.Z. Neuron-restrictive silencer factor-mediated hyperpolarization-activated cyclic nucleotide gated channelopathy in experimental temporal lobe epilepsy. Ann. Neurol., 2011, 70(3), 454-465.
[http://dx.doi.org/10.1002/ana.22479] [PMID: 21905079]
[60]
Zha, Q.; Brewster, A.L.; Richichi, C.; Bender, R.A.; Baram, T.Z. Activity-dependent heteromerization of the hyperpolarization-activated, cyclic-nucleotide gated (HCN) channels: role of N-linked glycosylation. J. Neurochem., 2008, 105(1), 68-77.
[http://dx.doi.org/10.1111/j.1471-4159.2007.05110.x] [PMID: 17988239]
[61]
Williams, A.D.; Jung, S.; Poolos, N.P. 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.
[http://dx.doi.org/10.1113/JP270453] [PMID: 25820761]
[62]
Concepcion, F.A.; Khan, M.N.; Ju Wang, J-D.; Wei, A.D.; Ojemann, J.G.; Ko, A.L.; Shi, Y.; Eng, J.K.; Ramirez, J-M.; Poolos, N.P. HCN channel phosphorylation sites mapped by mass spectrometry in human epilepsy patients and in an animal model of temporal lobe epilepsy. Neuroscience, 2021, 460, 13-30.
[http://dx.doi.org/10.1016/j.neuroscience.2021.01.038] [PMID: 33571596]
[63]
Peters, C.H.; Singh, R.K.; Bankston, J.R.; Proenza, C. Regulation of HCN Channels by Protein Interactions. Front. Physiol., 2022, 13, 928507.
[http://dx.doi.org/10.3389/fphys.2022.928507] [PMID: 35795651]
[64]
Savelieva, I.; Camm, A.J. I f inhibition with ivabradine: electrophysiological effects and safety. Drug Saf., 2008, 31(2), 95-107.
[http://dx.doi.org/10.2165/00002018-200831020-00001] [PMID: 18217787]
[65]
Iacone, Y.; Morais, T.P.; David, F.; Delicata, F.; Sandle, J.; Raffai, T.; Parri, H.R.; Weisser, J.J.; Bundgaard, C.; Klewe, I.V.; Tamás, G.; Thomsen, M.S.; Crunelli, V.; Lőrincz, M.L. Systemic administration of ivabradine, a hyperpolarization‐activated cyclic nucleotide‐gated channel inhibitor, blocks spontaneous absence seizures. Epilepsia, 2021, 62(7), 1729-1743.
[http://dx.doi.org/10.1111/epi.16926] [PMID: 34018186]
[66]
Inaba, Y.; Biagini, G.; Avoli, M. The H current blocker ZD7288 decreases epileptiform hyperexcitability in the rat neocortex by depressing synaptic transmission. Neuropharmacology, 2006, 51(3), 681-691.
[http://dx.doi.org/10.1016/j.neuropharm.2006.05.017] [PMID: 16806308]
[67]
Kitayama, M.; Miyata, H.; Yano, M.; Saito, N.; Matsuda, Y.; Yamauchi, T.; Kogure, S. Ih blockers have a potential of antiepileptic effects. Epilepsia, 2003, 44(1), 20-24.
[http://dx.doi.org/10.1046/j.1528-1157.2003.22702.x] [PMID: 12581225]
[68]
Matsuda, Y.; Saito, N.; Yamamoto, K.; Niitsu, T.; Kogure, S. Effects of the Ih blockers CsCl and ZD7288 on inherited epilepsy in Mongolian gerbils. Exp. Anim., 2008, 57(4), 377-384.
[http://dx.doi.org/10.1538/expanim.57.377] [PMID: 18633160]
[69]
Oyrer, J.; Bleakley, L.E.; Richards, K.L.; Maljevic, S.; Phillips, A.M.; Petrou, S.; Nowell, C.J.; Reid, C.A. Using a multiplex nucleic acid in situ hybridization technique to determine HCN4 mRNA expression in the adult rodent brain. Front. Mol. Neurosci., 2019, 12, 211.
[http://dx.doi.org/10.3389/fnmol.2019.00211] [PMID: 31555092]
[70]
Blumenfeld, H. Cellular and network mechanisms of spike-wave seizures. Epilepsia, 2005, 46(s9)(Suppl. 9), 21-33.
[http://dx.doi.org/10.1111/j.1528-1167.2005.00311.x] [PMID: 16302873]
[71]
Zobeiri, M.; Chaudhary, R.; Blaich, A.; Rottmann, M.; Herrmann, S.; Meuth, P.; Bista, P.; Kanyshkova, T.; Lüttjohann, A.; Narayanan, V.; Hundehege, P.; Meuth, S.G.; Romanelli, M.N.; Urbano, F.J.; Pape, H.C.; Budde, T.; Ludwig, A. The Hyperpolarization-Activated HCN4 Channel is Important for Proper Maintenance of Oscillatory Activity in the Thalamocortical System. Cereb. Cortex, 2019, 29(5), 2291-2304.
[http://dx.doi.org/10.1093/cercor/bhz047] [PMID: 30877792]
[72]
Kharouf, Q.; Phillips, A.M.; Bleakley, L.E.; Morrisroe, E.; Oyrer, J.; Jia, L.; Ludwig, A.; Jin, L.; Nicolazzo, J.A.; Cerbai, E.; Romanelli, M.N.; Petrou, S.; Reid, C.A. The hyperpolarization‐activated cyclic nucleotide‐gated 4 channel as a potential anti‐seizure drug target. Br. J. Pharmacol., 2020, 177(16), 3712-3729.
[http://dx.doi.org/10.1111/bph.15088] [PMID: 32364262]
[73]
Melchiorre, M.; Del Lungo, M.; Guandalini, L.; Martini, E.; Dei, S.; Manetti, D.; Scapecchi, S.; Teodori, E.; Sartiani, L.; Mugelli, A.; Cerbai, E.; Romanelli, M.N. Design, synthesis, and preliminary biological evaluation of new isoform-selective f-current blockers. J. Med. Chem., 2010, 53(18), 6773-6777.
[http://dx.doi.org/10.1021/jm1006758] [PMID: 20795648]
[74]
Del Lungo, M.; Melchiorre, M.; Guandalini, L.; Sartiani, L.; Mugelli, A.; Koncz, I.; Szel, T.; Varro, A.; Romanelli, M.N.; Cerbai, E. Novel blockers of hyperpolarization-activated current with isoform selectivity in recombinant cells and native tissue. Br. J. Pharmacol., 2012, 166(2), 602-616.
[http://dx.doi.org/10.1111/j.1476-5381.2011.01782.x] [PMID: 22091830]
[75]
McClure, K.J.; Maher, M.; Wu, N.; Chaplan, S.R.; Eckert, W.A., III; Lee, D.H.; Wickenden, A.D.; Hermann, M.; Allison, B.; Hawryluk, N.; Breitenbucher, J.G.; Grice, C.A. Discovery of a novel series of selective HCN1 blockers. Bioorg. Med. Chem. Lett., 2011, 21(18), 5197-5201.
[http://dx.doi.org/10.1016/j.bmcl.2011.07.051] [PMID: 21824780]
[76]
Kharouf, Q.; Pinares-Garcia, P.; Romanelli, M.N.; Reid, C.A. Testing broad-spectrum and isoform-preferring HCN channel blockers for anticonvulsant properties in mice. Epilepsy Res., 2020, 168, 106484.
[http://dx.doi.org/10.1016/j.eplepsyres.2020.106484] [PMID: 33099130]
[77]
Albertson, A.J.; Williams, S.B.; Hablitz, J.J. Regulation of epileptiform discharges in rat neocortex by HCN channels. J. Neurophysiol., 2013, 110(8), 1733-1743.
[http://dx.doi.org/10.1152/jn.00955.2012] [PMID: 23864381]
[78]
Arias, R.L.; Bowlby, M.R. Pharmacological characterization of antiepileptic drugs and experimental analgesics on low magnesium-induced hyperexcitability in rat hippocampal slices. Brain Res., 2005, 1047(2), 233-244.
[http://dx.doi.org/10.1016/j.brainres.2005.04.052] [PMID: 15907811]
[79]
Gill, C.H.; Brown, J.T.; Shivji, N.; Lappin, S.C.; Farmer, C.; Randall, A.; McNaughton, N.C.L.; Cobb, S.R.; Davies, C.H. Inhibition of Ih reduces epileptiform activity in rodent hippocampal slices. Synapse, 2006, 59(5), 308-316.
[http://dx.doi.org/10.1002/syn.20242] [PMID: 16421904]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy