CURRENT UNDERSTANDING OF HYPERPOLARIZATION-ACTIVATED AND CYCLIC NUCLEOTIDE-GATED (HCN) CHANNELS: A REVIEW
Keywords:
HCN ion channels, Arrythmia, Epilepsy, Neuropathic PainAbstract
Hyperpolarization-activated and Cyclic Nucleotide-gated (HCN) channels with significant physiological role are found to be present in heart and brain. These channels have got four subtypes encoded by four different genes. They play significant role in maintainance of cardiac rhythm and neuronal excitability with definite but partially defined role in development of arrhythmia, epilepsy and neuropathic pain. These are also known as pace maker channels. In present review we will mainly discuss electrophysiology of neurons and SA node in special reference to HCN channel. In the heart mainly HCN4 subtype is present while in brain all four isotype have been found where they are involved in numerous neuronal functions i.e. dendrite c integration, memory, thalamo-cortical rhythm etc. Further in review we will also discuss in brief the physiology and uniqueness of this ion channel and disorders especially epilepsy, neuropathic pain and cardiac arrhythmia, due to the malfunctioning of these ion channels. The newer possibilities of modifying this ion channel along with the drugs acting will also be discussed.
Keywords: HCN ion channels, Arrythmia, Epilepsy, Neuropathic Pain.
Downloads
References
Difrancesco D. Serious workings of the funny current. Prog Biophys Mol Biol 2006;90:13–25.
Biel M, Zong X, Ludwig A, Sautter A, and Hofmann F. Structure and function of cyclic nucleotide-gated channels. Rev Physiol Biochem Pharmacol 135:151–171.
Matulef K and Zagotta WN (2003) Cyclic nucleotide-gated ion channels. Annu Rev Cell Dev Biol 19:23–44.
Craven KB, Zagotta WN. CNG and HCN Channels: Two Peas, One Pod. Annu. Rev. Physiol. 2006. 68:375–401.
Santoro B et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci 2000;20:5264–5275.
Ishii TM, Takano M, Ohmori H. Determinants of activation kinetics in mammalian hyperpolarization-activated cation channels. J Physiol 537: 93–100, 2001.
Kaupp UB, Seifert R. Molecular diversity of pacemaker ion channels. Annu Rev Physiol 63: 235–257, 2001.
Milligan CJ, Edwards IJ, Deuchars J. HCN1 ion channel immunoreactivity in spinal cord and medulla oblongata. Brain Res 1081:79–91, 2006.
Moosmang S, Biel M, Hofmann F, Ludwig A. Differential distribution of four hyperpolarization-activated cation channels in mouse brain. Biol Chem 380: 975–980, 1999.
Notomi T, Shigemoto R. Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol 471: 241–276, 2004
Santoro B et al. Molecular and functional heterogeneity of hyperpolarization-activated pacemaker channels in the mouse CNS. J Neurosci 20: 5264–5275, 2000.
Santoro B, Grant SG, Bartsch D, Kandel ER. Interactive cloning with the SH3 domain of N-src identifies a new brain specific ion channel protein, with homology to eag and cyclic nucleotide-gated channels. Proc Natl Acad Sci USA 94: 14815–14820, 1997.
Moosmang S et al. Cellular expression and functional characterization of four hyperpolarization- activated pacemaker channels in cardiac and neuronal tissues. Eur J Biochem 268: 1646–1652, 2001.
Dobrzynski H. et al. Site of origin and molecular substrate of atrioventricular rhythm in the rabbit heart. Circ Res 93: 1102–1110, 2003.
Shi W, Yu H, Wu J, Zuckerman J, Wymore R. The distribution and prevalence of HCN isoforms in the canine heart and their relation to voltage dependence of If. Biophys J 78: e353A, 2000.
Ludwig, A., X. Zong, M. Jeglitsch, F. Hofmann, and M. Biel. 1998. A family of hyperpolarization-activated mammalian cation channels.Nature. 393:587–591.
Laio, A., and V. Torre. 1999. Physical origin of selectivity in ionic channels of biological membranes. Biophys. J. 76:129–148.
DiFrancesco D. The role of the funny current in pacemaker activity. Circ Res 2010;106:434–446.
Maltsev VA, Lakatta EG. Dynamic interactions of an intracellular Ca2+ clock and membrane ion channel clock underlie robust initiation and regulation of cardiac pacemaker function. Cardiovasc Res 2008;77:274–284.
Noma, A. Ionic mechanisms of the cardiac pacemaker potential Jpn. Heart J. 37, 673–682.
Hagiwara, N., Irisawa, H. & Kameyama, M. Contribution of two types of calcium currents to the pacemaker potentials of rabbit sino-atrial node cells. J. Physiol. 395, 233–253.
Mangoni, M. E. & Nargeot, J. Properties of the hyperpolarization-activated current (I(f)) in isolated mouse sino-atrial cells. (2001) Cardiovasc. Res. 52, 51–64.
Stieber J, Herrmann S, Feil S, Loster J, Feil R, Biel M, Hofmann F, et al. The hyperpolarization-activated channel HCN4 is required for the generation of pacemaker action potentials in the embryonic heart. Proc Natl Acad Sci USA. 2003;100:15235–15240.
Herrmann S, Stieber J, Stockl G, Hofmann F, Ludwig A. HCN4 provides a ‘depolarization reserve’ and is not required for heart rate acceleration in mice. EMBO J. 2007;26:4423–4432.
Ludwig A. et al. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J 22: 216–224, 2003.
Nolan MF, Dudman JT, Dodson PD, Santoro B. HCN1 channels from layer II of the entorhinal cortex. J Neurosci 27: 12440–12451, 2007.
Notomi T, Shigemoto R (2004) Immunohistochemical localization of Ih channel subunits, HCN1-4, in the rat brain. J Comp Neurol 471:
-276.
Nolan MF. et al. A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119: 719–732, 2004.
Tsay D, Dudman JT, Siegelbaum SA. HCN1 channels constrain
synaptically evoked Ca2_ spikes in distal dendrites of CA1 pyramidal
neurons. Neuron 56: 1076–1089, 2007.
Wang M. et al. Alpha2A-adrenoceptors strengthen working memory networks by inhibiting cAMP-HCN channel signaling in prefrontal cortex. Cell 129: 397–410, 2007.
Nolan MF. et al. The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell 115: 551–564, 2003.
Magee JC. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J Neurosci 18: 7613–7624, 1998.
McCormick DA, Bal T. Sleep and arousal: thalamocortical mechanisms. Annu Rev Neurosci 20: 185–215, 1997.
Gray CM, Singer W. Stimulus-specific neuronal oscillations in orientation columns of cat visual cortex. Proc Natl Acad Sci USA 86: 1698–1702, 1989.
McCormick DA, Contreras D. On the cellular and network bases of epileptic seizures. Annu Rev Physiol 63: 815–846, 2001.
Jung S. et al. Downregulation of Dendritic HCN Channel Gating in Epilepsy Is Mediated by Altered Phosphorylation Signaling. The Journal of Neuroscience, 2010•30(19):6678 – 6688
Du L. et al. The role of HCN channels within the periaqueductal gray in neuropathic pain. Brain Res. 2013 Mar 15;1500:36-44
Chen K. et al. Persistently modified h-channels after complex febrile seizures convert the seizure-induced enhancement of inhibition to hyperexcitability. Nat Med. 2001;7:331–337.
Zhang K, Peng BW, Sanchez RM (2006) Decreased Ih in hippocampal area CA1 pyramidal neurons after perinatal seizure-inducing hypoxia. Epilepsia 47:1023–1028.
Wierschke S, Lehmann TN, Dehnicke C, Horn P, Nitsch R, Deisz RA (2010) Hyperpolarization-activated cation currents in human epileptogenic neocortex. Epilepsia 51:404 –414.
Huang Z, Walker MC, Shah MM (2009) Loss of dendritic HCN1 subunits enhances cortical excitability and epileptogenesis. J Neurosci 29:10979 –10988.
DiFrancesco JC. et al., Recessive loss-of-function mutation in the pacemaker HCN2 channel causing increased neuronal excitability in a patient with idiopathic generalized epilepsy,†The Journal of Neuroscience,31:48, 17327–17337, 2011.
Reid CA. et al. HCN channelopathies: pathophysiology in genetic epilepsy and therapeutic implications,†British Journal of Pharmacology, vol. 165:1,49–56, 2012.
Bender RA. et al. 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;23:6826–6836.
Liu CN, Michaelis M, Amir R, Devor M (2000) Spinal nerve injury enhances subthreshold membrane potential oscillations in DRG neurons: relation to neuropathic pain. J Neurophysiol 84:205–215.
Mayer ML, Westbrook GL (1983) A voltage-clamp analysis of inward (anomalous) rectification in mouse spinal sensory ganglion neurones. J Physiol (Lond) 340:19–45.
Sun Q, Xing GG, Tu HY, Han JS, Wan Y. Inhibition of hyperpolarization-activated current by ZD7288 suppresses ectopic discharges of injured dorsal root ganglion neuron. Brain research 1032:1-2; 25:63-9
Chaplan SR, Guo HQ, Lee DH, et al. Neuronal hyperpolarization-activated
pacemaker channels drive neuropathic pain. J Neurosci 2003; 23:1169–1178
Emery EC.et al. HCN2 Ion Channels Play a Central Role in Inflammatory and Neuropathic Pain. 2011 Science: 333 (6048) 1462-1466
Luo L. et al. Role of peripheral hyperpolarization-activated cyclic nucleotide-modulated channel pacemaker channels in acute and chronic pain models in the rat. Neuroscience 144 (2007) 1477–1485.
Dalle C. Eisenach JC. Peripheral block of the hyperpolarization-activated cation current (Ih) reduces mechanical allodynia in animal models of postoperative and neuropathic pain. Reg Anesth Pain Med. 2005 May-Jun;30(3):243-8
Milanesi, R.; Baruscotti, M.; Gnecchi-Ruscone, T.; DiFrancesco, D. Familial sinus bradycardia associated with a mutation in the cardiac pacemaker channel. N. Engl. J. Med. 2006, 354, 151–157.
Baruscotti, M.; Bottelli, G.; Milanesi, R.; DiFrancesco, J.C.; DiFrancesco, D. HCN-related channelopathies. Pflugers Arch. 2010, 460, 405–415.
Kuwabara Y. et al. HCN Overexpression in Failing Heart Possibly Contributes to Ventricular Arrhythmias. Circ Res.2012;111:A331.
Ueda K. et al. Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia. J Biol Chem. 2004 25;279(26):27194-8
Ueda K. et al. Role of HCN4 channel in preventing ventricular arrhythmiaRole of HCN4 channel in ventricular arrhythmia. Journal of Human Genetics 2009 54, 115-121.
Bucchi, A.; Baruscotti, M.; DiFrancesco, D. Current-dependent block of rabbit sino-atrial node If channels by ivabradine. J. Gen. Physiol. 2002, 120, 1–13.
Tardif JC, Ford I, Tendera M, Bourassa MG, Fox K. "Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina". Eur. Heart J. 26(23): 2529–36
Ruzyllo W, Tendera M, Ford I, Fox KM. "Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial". Drugs. 67(3): 393–405
Fox K. et al. "Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction: a randomised, double-blind, placebo-controlled trial". The Lancet 372 (9641): 807–816.
Swedberg K, Komajda M, Böhm M, Borer JS, Ford I, Dubost-Brama A, Lerebours G, Tavazzi L; on behalf of the SHIFT Investigators (2010). "Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study". The Lancet 376 (9744): 875–885
Ptaszynski P. et al. Ivabradine in Combination With Metoprolol Succinate in the Treatment of Inappropriate Sinus Tachycardia. J cardiovasc pharmacol ther. 2013.: 1074248413478172
Du, Lu; Wang, Shao-Jun; Cui, Jian; He, Wen-Juan; Ruan, Huai-Zhen. Inhibition of HCN channels within the periaqueductal gray attenuates neuropathic pain in rats. Behavioral Neuroscience, Vol 127(2), Apr 2013, 325-329.
Jiang YQ, Xing GG, Wang SL, et al. Axonal accumulation of hyperpolarization-activated cyclic nucleotide-gated cation channels contributes to mechanical allodynia after peripheral nerve injury in rat. Pain 2008;137:495–506.
Harrison’s Principle of Internal Medicine. 18th edition. Chapter 369.
Jung S, Warner LN, Pitsch J, Becker AJ, Poolos NP. Rapid Loss of Dendritic HCN Channel Expression in Hippocampal Pyramidal Neurons Following Status Epilepticus. J Neurosci 2011;31(40):14291–4295.
Dibbens LM, Reid CA, Hodgson B, Thomas EA, Phillips AM, Gazina E et al. (2010). Augmented currents of an HCN2 variant in patients with febrile seizure syndromes. Ann Neurol 67: 542–546.
Poolos NP, Migliore M, Johnston D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nat Neurosci 5: 767–774.
Surges R, Freiman TM, Feuerstein TJ. Gabapentin increases the hyperpolarization-activated cation current Ih in rat CA1 pyramidal cells. Epilepsia 44: 150–156.
Chen X, Shu S,Bayliss DA. HCN1 channel subunits are a molecular substrate for hypnotic actions of ketamine. J Neurosci. 2009 January 21; 29(3): 600–609.
Lyashchenko AK, Redd KJ, Yang J, Tibbs GR (2007). Propofol inhibits HCN1 pacemaker channels by selective association with the closed states of the membrane embedded channel core. J Physiol 583: 37–56.
Cacheaux LP. et al. Impairment of Hyperpolarization-Activated, Cyclic NucleotideGated Channel Function by the Intravenous General Anesthetic Propofol. JPET 315:517–525.
Published
How to Cite
Issue
Section
The publication is licensed under CC By and is open access. Copyright is with author and allowed to retain publishing rights without restrictions.