Skip to content
Licensed Unlicensed Requires Authentication Published by De Gruyter February 15, 2019

Hyperpolarization-activated and cyclic nucleotide-gated channel proteins as emerging new targets in neuropathic pain

Jin-Ting He, Xiao-Yan Li, Xin Zhao and Xiaoliang Liu

Abstract

Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are activated during hyperpolarization, and there is an inward flow of current, which is termed as hyperpolarization-activated current, Ih. Initially, these channels were identified on the pacemaker cells of the heart. Nowadays, these are identified on different regions of the nervous system, including peripheral nerves, dorsal root ganglia, dorsal horns, and different parts of the brain. There are four different types of HCN channels (HCN1–HCN4); however, HCN1 and HCN2 are more prominent. A large number of studies have shown that peripheral nerve injury increases the amplitude of Ih current in the neurons of the spinal cord and the brain. Moreover, there is an increase in the expression of HCN1 and HCN2 protein channels in peripheral axons and the spinal cord and brain regions in experimental models of nerve injury. Studies have also documented the pain-attenuating actions of selective HCN inhibitors, such as ivabradine and ZD7288. Moreover, certain drugs with additional HCN-blocking activities have also shown pain-attenuating actions in different pain models. There have been few studies documenting the relationship of HCN channels with other mediators of pain. Nevertheless, it may be proposed that the HCN channel activity is modulated by endogenous opioids and cyclo-oxygenase-2, whereas the activation of these channels may modulate the actions of substance P and the expression of spinal N-methyl-D-aspartate receptor subunit 2B to modulate pain. The present review describes the role and mechanisms of HCN ion channels in the development of neuropathic pain.

Funding source: Jilin Provincial Department of Finance Funds in China

Award Identifier / Grant number: Sczsy 201512

Funding source: Jilin Provincial Department of Health Funds

Award Identifier / Grant number: 20152085

Funding source: The National Natural Science Fund Projects

Award Identifier / Grant number: 81671159

Funding source: Jilin Province Department of International Cooperation Projects

Award Identifier / Grant number: 20170414014GH

Funding source: Jilin University Outstanding Young Teacher Training Program

Award Identifier / Grant number: 450060472325

Funding statement: This project was supported by the Jilin Provincial Department of Finance Funds in China (No. Sczsy 201512), the Jilin Provincial Department of Health Funds (No. 20152085), The National Natural Science Fund Projects (No. 81671159), the Jilin Province Department of International Cooperation Projects (No. 20170414014GH), and the Jilin University Outstanding Young Teacher Training Program (No. 450060472325).

References

Antal, M., Papp, I., Bahaerguli, N., Veress, G., and Vereb, G. (2004). Expression of hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 in axon terminals of peptidergic nociceptive primary sensory neurons in the superficial spinal dorsal horn of rats. Eur. J. Neurosci. 19, 1336–1342.10.1111/j.1460-9568.2004.03235.xSearch in Google Scholar PubMed

Balakrishnan, S. and Mironov, S.L. (2018). Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization. PLoS One 13, e0195094.10.1371/journal.pone.0195094Search in Google Scholar PubMed PubMed Central

Bernal, L. and Roza, C. (2018). Hyperpolarization-activated channels shape temporal patterns of ectopic spontaneous discharge in C-nociceptors after peripheral nerve injury. Eur. J. Pain. doi: 10.1002/ejp.1226. [Epub ahead of print].10.1002/ejp.1226Search in Google Scholar PubMed

Brennan, G.P., Baram, T.Z., and Poolos, N. P. (2016). Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in epilepsy. Cold Spring Harb. Perspect. Med. 6, a022384.10.1101/cshperspect.a022384Search in Google Scholar PubMed PubMed Central

Brummett, C.M., Hong, E.K., Janda, A.M., Amodeo, F.S., and Lydic, R. (2011). Perineural dexmedetomidine added to ropivacaine for sciatic nerve block in rats prolongs the duration of analgesia by blocking the hyperpolarization-activated cation current. Anesthesiology 115, 836–843.10.1097/ALN.0b013e318221fcc9Search in Google Scholar PubMed PubMed Central

Burke, N.N., Kerr, D.M., Moriarty, O., Finn, D.P., and Roche, M. (2014). Minocycline modulates neuropathic pain behaviour and cortical M1-M2 microglial gene expression in a rat model of depression. Brain Behav. Immun. 42, 147–156.10.1016/j.bbi.2014.06.015Search in Google Scholar PubMed

Cacheaux, L.P., Topf, N., Tibbs, G.R., Schaefer, U.R., Levi, R., Harrison, N.L., Abbott, G.W., and Goldstein, P.A. (2005). Impairment of hyperpolarization-activated, cyclic nucleotide-gated channel function by the intravenous general anesthetic propofol. J. Pharmacol. Exp. Ther. 315, 517–525.10.1124/jpet.105.091801Search in Google Scholar PubMed

Cao, D.N., Song, R., Zhang, S.Z., Wu, N., and Li, J. (2016). Nucleus accumbens hyperpolarization-activated cyclic nucleotide-gated channels modulate methamphetamine self-administration in rats. Psychopharmacology (Berl.) 233, 3017–3029.10.1007/s00213-016-4349-zSearch in Google Scholar PubMed

Chan, C.S., Shigemoto, R., Mercer, J.N., and Surmeier, D.J. (2004). HCN2 and HCN1 channels govern the regularity of autonomous pacemaking and synaptic resetting in globus pallidus neurons. J. Neurosci. 24, 9921–9932.10.1523/JNEUROSCI.2162-04.2004Search in Google Scholar PubMed PubMed Central

Chaplan, S.R., Guo, H.Q., Lee, D.H., Luo, L., Liu, C., Kuei, C., Velumian, A.A., Butler, M.P., Brown, S.M., and Dubin, A.E. (2003). Neuronal hyperpolarization-activated pacemaker channels drive neuropathic pain. J. Neurosci. 23, 1169–1178.10.1523/JNEUROSCI.23-04-01169.2003Search in Google Scholar

Chen, X., Shu, S., and Bayliss, D.A. (2005). Suppression of Ih contributes to propofol induced inhibition of mouse cortical pyramidal neurons. J. Neurophysiol. 94, 3872–3883.10.1152/jn.00389.2005Search in Google Scholar PubMed

Cho, H.J., Staikopoulos, V., Furness, J.B., and Jennings, E.A. (2009). Inflammation-induced increase in hyperpolarization-activated, cyclic nucleotide-gated channel protein in trigeminal ganglion neurons and the effect of buprenorphine. Neuroscience 162, 453–461.10.1016/j.neuroscience.2009.04.063Search in Google Scholar PubMed

Cordeiro Matos, S., Zhang, Z., and Séguéla, P. (2015). Peripheral neuropathy induces HCN channel dysfunction in pyramidal neurons of the medial prefrontal cortex. J. Neurosci. 35, 13244–13256.10.1523/JNEUROSCI.0799-15.2015Search in Google Scholar PubMed PubMed Central

Descoeur, J., Pereira, V., Pizzoccaro, A., Francois, A., Ling, B., Maffre, V., Couette, B., Busserolles, J., Courteix, C., Noel, J., et al. (2011). Oxaliplatin-induced cold hypersensitivity is due to remodelling of ion channel expression in nociceptors. EMBO Mol. Med. 3, 266–278.10.1002/emmm.201100134Search in Google Scholar PubMed PubMed Central

DiFrancesco, D. and Ojeda, C. (1980). Properties of the current if in the sino-atrial node of the rabbit compared with those of the current iK2, in Purkinje fibres. J. Physiol. 308, 353–367.10.1113/jphysiol.1980.sp013475Search in Google Scholar PubMed PubMed Central

Ding, W., You, Z., Shen, S., Chen, L., Zhu, S., and Mao, J. (2016). Inhibition of HCN channel activity in the thalamus attenuates chronic pain in rats. Neurosci. Lett. 631, 97–103.10.1016/j.neulet.2016.08.021Search in Google Scholar PubMed PubMed Central

Ding, W., You, Z., Shen, S., Yang, J., Lim, G., Doheny, J.T., Zhu, S., Zhang, Y., Chen, L., and Mao, J. (2018). Increased HCN channel activity in the Gasserian ganglion contributes to trigeminal neuropathic pain. J. Pain 19, 626–634.10.1016/j.jpain.2018.01.003Search in Google Scholar PubMed PubMed Central

Du, L., Wang, S.J., Cui, J., He, W.J., and Ruan, H.Z. (2013a). Inhibition of HCN channels within the periaqueductal gray attenuates neuropathic pain in rats. Behav. Neurosci. 127, 325–329.10.1037/a0031893Search in Google Scholar PubMed

Du, L., Wang, S.J., Cui, J., He, W.J., and Ruan, H.Z. (2013b). The role of HCN channels within the periaqueductal gray in neuropathic pain. Brain Res. 1500, 36–44.10.1016/j.brainres.2013.01.035Search in Google Scholar PubMed

Emery, E.C., Young, G.T., Berrocoso, E.M., Chen, L., and McNaughton, P.A. (2011). HCN2 ion channels play a central role in inflammatory and neuropathic pain. Science 333, 1462–1466.10.1126/science.1206243Search in Google Scholar PubMed

Fala, L. (2016). Corlanor (ivabradine), first HCN channel blocker, FDA approved for the treatment of patients with heart failure. Am. Health Drug Benefits 9, 56–59.Search in Google Scholar

Gill, C.H., Randall, A., Bates, S.A., Hill, K., Owen, D., Larkman, P.M., Cairns, W., Yusaf, S.P., Murdock, P.R., Strijbos, P.J., et al. (2004). Characterization of the human HCN1 channel and its inhibition by capsazepine. Br. J. Pharmacol. 143, 411–421.10.1038/sj.bjp.0705945Search in Google Scholar PubMed PubMed Central

González-Rodríguez, S., Álvarez, M.G., García-Domínguez, M., Lastra, A., Cernuda-Cernuda, R., Folgueras, A.R., Fernández-García, M.T., Hidalgo, A., Baamonde, A., and Menéndez, L. (2017). Hyperalgesic and hypoalgesic mechanisms evoked by the acute administration of CCL5 in mice. Brain Behav. Immun. 62, 151–161.10.1016/j.bbi.2017.01.014Search in Google Scholar PubMed

Hatch, R.J., Jennings, E.A., and Ivanusic, J.J. (2013). Peripheral hyperpolarization-activated cyclic nucleotide-gated channels contribute to inflammation-induced hypersensitivity of the rat temporomandibular joint. Eur. J. Pain 17, 972–982.10.1002/j.1532-2149.2012.00261.xSearch in Google Scholar PubMed

Jessell, T.M. (1982). Substance P in nociceptive sensory neurons. Ciba Found. Symp. 91, 225–248.10.1002/9780470720738.ch13Search in Google Scholar PubMed

Jiang, Y.Q., Sun, Q., Tu, H.Y., and Wan, Y. (2008a). Characteristics of HCN channels and their participation in neuropathic pain. Neurochem. Res. 33, 1979–1989.10.1007/s11064-008-9717-6Search in Google Scholar PubMed

Jiang, Y.Q., Xing, G.G., Wang, S.L., Tu, H.Y., Chi, Y.N., Li, J., Liu, F.Y., Han, J.S., and Wan, Y. (2008b). Axonal accumulation of hyperpolarization-activated cyclic nucleotide-gated cation channels contributes to mechanical allodynia after peripheral nerve injury in rat. Pain 137, 495–506.10.1016/j.pain.2007.10.011Search in Google Scholar PubMed

Kaupp, U.B. and Seifert, R. (2001). Molecular diversity of pacemaker ion channels. Annu. Rev. Physiol. 63, 235–257.10.1146/annurev.physiol.63.1.235Search in Google Scholar PubMed

Ku, S.M. and Han, M.H. (2017). HCN channel targets for novel antidepressant treatment. Neurotherapeutics 14, 698–715.10.1007/s13311-017-0538-7Search in Google Scholar PubMed PubMed Central

Lee, C.H. and MacKinnon, R. (2017). Structures of the human HCN1 hyperpolarization-activated channel. Cell 168, 111e.11–120.e11.10.1016/j.cell.2016.12.023Search in Google Scholar PubMed PubMed Central

Lee, D.H., Chang, L., Sorkin, L.S., and Chaplan, S.R. (2005). Hyperpolarization-activated, cation-nonselective, cyclic nucleotide-modulated channel blockade alleviates mechanical allodynia and suppresses ectopic discharge in spinal nerve ligated rats. J. Pain 6, 417–424.10.1016/j.jpain.2005.02.002Search in Google Scholar PubMed

Liu, N., Zhang, D., Zhu, M., Luo, S., and Liu, T. (2015). Minocycline inhibits hyperpolarization-activated currents in rat substantia gelatinosa neurons. Neuropharmacology 95, 110–120.10.1016/j.neuropharm.2015.03.001Search in Google Scholar

Liu, H., Zhou, J., Gu, L., and Zuo, Y. (2017). The change of HCN1/HCN2 mRNA expression in peripheral nerve after chronic constriction injury induced neuropathy followed by pulsed electromagnetic field therapy. Oncotarget 8, 1110–1116.10.18632/oncotarget.13584Search in Google Scholar

Liu, X., Zhang, L., Jin, L., Tan, Y., Li, W., and Tang, J. (2018). HCN2 contributes to oxaliplatin-induced neuropathic pain through activation of the CaMKII/CREB cascade in spinal neurons. Mol. Pain. 14, 1744806918778490.10.1177/1744806918778490Search in Google Scholar

Ludwig, A., Zong, X., Jeglitsch, M., Hofmann, F., and Biel, M. (1998). A family of hyperpolarization-activated mammalian cation channels. Nature 393, 587–591.10.1038/31255Search in Google Scholar

Luo, L., Chang, L., Brown, S.M., Ao, H., Lee, D.H., Higuera, E.S., Dubin, A.E., and Chaplan, S.R. (2007). Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. Neuroscience 144, 1477–1485.10.1016/j.neuroscience.2006.10.048Search in Google Scholar

Maroso, M., Szabo, G.G., Kim, H.K., Alexander, A., Bui, A.D., Lee, S.H., Lutz, B., and Soltesz, I. (2016). Cannabinoid control of learning and memory through HCN channels. Neuron 89, 1059–1073.10.1016/j.neuron.2016.01.023Search in Google Scholar

Martinez, V., Szekely, B., Lemarié, J., Martin, F., Gentili, M., Ben Ammar, S., Lepeintre, J.F., Garreau de Loubresse, C., Chauvin, M., Bouhassira, D., et al. (2013). The efficacy of a glial inhibitor, minocycline, for preventing persistent pain after lumbar discectomy: a randomized, double-blind, controlled study. Pain 154, 1197–1203.10.1016/j.pain.2013.03.028Search in Google Scholar

Momin, A., Cadiou, H., Mason, A., and McNaughton, P.A. (2008). Role of the hyperpolarization-activated current Ih in somatosensory neurons. J. Physiol. 586, 5911–5929.10.1113/jphysiol.2008.163154Search in Google Scholar

Morani, A.S. and Bodhankar, S.L. (2010). Early co-administration of vitamin E acetate and methylcobalamin improves thermal hyperalgesia and motor nerve conduction velocity following sciatic nerve crush injury in rats. Pharmacol. Rep. 62, 405–409.10.1016/S1734-1140(10)70281-4Search in Google Scholar

Noh, S., Kumar, N., Bukhanova, N., Chen, Y., Stemkowsi, P.L., and Smith, P.A. (2014). The heart-rate-reducing agent, ivabradine, reduces mechanical allodynia in a rodent model of neuropathic pain. Eur. J. Pain 18, 1139–1147.10.1002/j.1532-2149.2014.00460.xSearch in Google Scholar PubMed

Obreja, O., Klusch, A., Ponelies, N., Schmelz, M., and Petersen, M. (2008). A subpopulation of capsaicin-sensitive porcine dorsal root ganglion neurons is lacking hyperpolarization-activated cyclic nucleotide-gated channels. Eur. J. Pain 12, 775–789.10.1016/j.ejpain.2007.11.010Search in Google Scholar

Occhiuto, F., Palumbo, D.R., Samperi, S., Zangla, G., Pino, A., De Pasquale, R., and Circosta, C. (2009). The isoflavones mixture from Trifolium pratense L. protects HCN 1-A neurons from oxidative stress. Phytother. Res. 23, 192–196.10.1002/ptr.2584Search in Google Scholar

Papp, I., Szucs, P., Holló, K., Erdélyi, F., Szabó, G., and Antal, M. (2006). Hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 ion channels modulate synaptic transmission from nociceptive primary afferents containing substance P to secondary sensory neurons in laminae I-IIo of the rodent spinal dorsal horn. Eur. J. Neurosci. 24, 1341–1352.10.1111/j.1460-9568.2006.05013.xSearch in Google Scholar

Papp, I., Holló, K., and Antal, M. (2010). Plasticity of hyperpolarization-activated and cyclic nucleotide-gated cation channel subunit 2 expression in the spinal dorsal horn in inflammatory pain. Eur. J. Neurosci. 32, 1193–1201.10.1111/j.1460-9568.2010.07370.xSearch in Google Scholar

Peng, S.C., Wu, J., Zhang, D.Y., Jiang, C.Y., Xie, C.N., and Liu, T. (2017). Contribution of presynaptic HCN channels to excitatory inputs of spinal substantia gelatinosa neurons. Neuroscience 358, 146–157.10.1016/j.neuroscience.2017.06.046Search in Google Scholar

Pires da Silva, M., de Almeida Moraes, D.J., Mecawi, A.S., Rodrigues, J.A., and Varanda, W.A. (2016). Nitric oxide modulates HCN channels in magnocellular neurons of the supraoptic nucleus of rats by an S-nitrosylation-dependent mechanism. J. Neurosci. 36, 11320–11330.10.1523/JNEUROSCI.1588-16.2016Search in Google Scholar

Resta, F., Masi, A., Sili, M., Laurino, A., Moroni, F., and Mannaioni, G. (2016). Kynurenic acid and zaprinast induce analgesia by modulating HCN channels through GPR35 activation. Neuropharmacology 108, 136–143.10.1016/j.neuropharm.2016.04.038Search in Google Scholar

Resta, F., Micheli, L., Laurino, A., Spinelli, V., Mello, T., Sartiani, L., Di Cesare Mannelli, L., Cerbai, E., Ghelardini, C., Romanelli, M.N., et al. (2018). Selective HCN1 block as a strategy to control oxaliplatin-induced neuropathy. Neuropharmacology 131, 403–413.10.1016/j.neuropharm.2018.01.014Search in Google Scholar

Rivera-Arconada, I., Roza, C., and Lopez-Garcia, J.A. (2013). Characterization of hyperpolarization-activated currents in deep dorsal horn neurons of neonate mouse spinal cord in vitro. Neuropharmacology 70, 148–155.10.1016/j.neuropharm.2013.01.019Search in Google Scholar

Santoro, B., Liu, D.T., Yao, H., Bartsch, D., Kandel, E.R., Siegelbaum, S.A., and Tibbs, G.R. (1998). Identification of a gene encoding a hyperpolarization-activated pacemaker channel of brain. Cell 93, 717–729.10.1016/S0092-8674(00)81434-8Search in Google Scholar

Santos, F.M., Silva, J.T., Rocha, I.R.C., Martins, D.O., and Chacur, M. (2018). Non-pharmacological treatment affects neuropeptide expression in neuropathic pain model. Brain Res. 1687, 60–65.10.1016/j.brainres.2018.02.034Search in Google Scholar PubMed

Schnorr, S., Eberhardt, M., Kistner, K., Rajab, H., Käßer, J., Hess, A., Reeh, P., Ludwig, A., and Herrmann, S. (2014). HCN2 channels account for mechanical (but not heat) hyperalgesia during long-standing inflammation. Pain 155, 1079–1090.10.1016/j.pain.2014.02.006Search in Google Scholar PubMed

Stadler, K., Bierwirth, C., Stoenica, L., Battefeld, A., Reetz, O., Mix, E., Schuchmann, S., Velmans, T., Rosenberger, K., Bräuer, A.U., et al. (2014). Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations. Cereb. Cortex 24, 199–210.10.1093/cercor/bhs305Search in Google Scholar PubMed

Sun, W., Yang, F., Wang, Y., Fu, H., Yang, Y., Li, C.L., Wang, X.L., Lin, Q., and Chen, J. (2017). Contribution of large-sized primary sensory neuronal sensitization to mechanical allodynia by upregulation of hyperpolarization-activated cyclic nucleotide gated channels via cyclooxygenase 1 cascade. Neuropharmacology 113, 217–230.10.1016/j.neuropharm.2016.10.012Search in Google Scholar PubMed

Takasu, K., Ono, H., and Tanabe, M. (2010). Spinal hyperpolarization-activated cyclic nucleotide-gated cation channels at primary afferent terminals contribute to chronic pain. Pain 151, 87–96.10.1016/j.pain.2010.06.020Search in Google Scholar PubMed

Tibbs, G.R., Rowley, T.J., Sanford, R.L., Herold, K.F., Proekt, A., Hemmings, H.C. Jr, Andersen, O.S., Goldstein, P.A., and Flood, P.D. (2013). HCN1 channels as targets for anesthetic and nonanesthetic propofol analogs in the amelioration of mechanical and thermal hyperalgesia in a mouse model of neuropathic pain. J. Pharmacol. Exp. Ther. 345, 363–373.10.1124/jpet.113.203620Search in Google Scholar PubMed PubMed Central

Tsantoulas, C., Laínez, S., Wong, S., Mehta, I., Vilar, B., and McNaughton, P.A. (2017). Hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) ion channels drive pain in mouse models of diabetic neuropathy. Sci. Transl. Med. 9, eaam6072.10.1126/scitranslmed.aam6072Search in Google Scholar PubMed PubMed Central

Wan, Y. (2008). Involvement of hyperpolarization-activated, cyclic nucleotide-gated cation channels in dorsal root ganglion in neuropathic pain. Sheng Li Xue Bao 60, 579–580.Search in Google Scholar

Wang, L., Dufour, S., Valiante, T.A., and Carlen, P.L. (2016). Extracellular Potassium and Seizures: Excitation, Inhibition and the Role of Ih. Int. J. Neural Syst. 26, 1650044.10.1142/S0129065716500441Search in Google Scholar PubMed

Weerasinghe, D., Menon, P., and Vucic, S. (2017). Hyperpolarization-activated cyclic-nucleotide-gated channels potentially modulate axonal excitability at different thresholds. J. Neurophysiol. 118, 3044–3050.10.1152/jn.00576.2017Search in Google Scholar PubMed PubMed Central

Wells, J.E., Rowland, K.C., and Proctor, E.K. (2007). Hyperpolarization-activated channels in trigeminal ganglia innervating healthy and pulp-exposed teeth. Int. Endod. J. 40, 715–721.10.1111/j.1365-2591.2007.01297.xSearch in Google Scholar PubMed

Weng, X.C. and Liu, S.J. (2014). Role of HCN channels in the nervous system: membrane excitability and various modulations. Zhongguo Ying Yong Sheng Li Xue Za Zhi 30, 506–510.Search in Google Scholar

Xie, R.G., Chu, W.G., Hu, S.J., and Luo, C. (2018). Characterization of different types of excitability in large somatosensory neurons and its plastic changes in pathological pain states. Int. J. Mol. Sci. 19, pii: E161.10.3390/ijms19010161Search in Google Scholar PubMed PubMed Central

Yeon, K.Y., Chung, G., Kim, Y.H., Hwang, J.H., Davies, A.J., Park, M.K., Ahn, D.K., Kim, J.S., Jung, S.J., and Oh, S.B. (2011). Eugenol reverses mechanical allodynia after peripheral nerve injury by inhibiting hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Pain 152, 2108–2116.10.1016/j.pain.2011.05.018Search in Google Scholar PubMed

Zhang, M., Han, W., Zheng, J., Meng, F., Jiao, X., Hu, S., and Xu, H. (2015). Inhibition of hyperpolarization-activated cation current in medium-sized DRG neurons contributed to the antiallodynic effect of methylcobalamin in the rat of a chronic compression of the DRG. Neural Plast. 2015, 197392.10.1155/2015/197392Search in Google Scholar PubMed PubMed Central

Zhang, K., Xu, T., Yuan, Z., Wei, Z., Yamaki, V.N., Huang, M., Huganir, R.L., and Cai, X. (2016a). Essential roles of AMPA receptor GluA1 phosphorylation and presynaptic HCN channels in fast-acting antidepressant responses of ketamine. Sci. Signal. 9, ra123.10.1126/scisignal.aai7884Search in Google Scholar PubMed PubMed Central

Zhang, S., You, Z., Wang, S., Yang, J., Yang, L., Sun, Y., Mi, W., Yang, L., McCabe, M.F., Shen, S., et al. (2016b). Neuropeptide S modulates the amygdaloidal HCN activities (Ih) in rats: implication in chronic pain. Neuropharmacology 105, 420–433.10.1016/j.neuropharm.2016.02.004Search in Google Scholar PubMed

Zúñiga, R., González, D., Valenzuela, C., Brown, N., and Zúñiga, L. (2016). Expression and cellular localization of HCN channels in rat cerebellar granule neurons. Biochem. Biophys. Res. Commun. 478, 1429–1435.10.1016/j.bbrc.2016.08.141Search in Google Scholar PubMed

Zuo, G.F., Li, M.H., Zhang, J.X., Li, B., Wang, Z.M., Wang, Q., Xiao, H., and Chen, S.L. (2013). Capsazepine concentration dependently inhibits currents in HEK 293 cells mediated by human hyperpolarization-activated cyclic nucleotide-gated 2 and 4 channels. Exp. Biol. Med. (Maywood) 238, 1055–1061.10.1177/1535370213498973Search in Google Scholar PubMed

Received: 2018-09-12
Accepted: 2018-10-26
Published Online: 2019-02-15
Published in Print: 2019-07-26

©2019 Walter de Gruyter GmbH, Berlin/Boston

Scroll Up Arrow