Hypothalamic Ion Channels in Hypertension
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Hypertension is a prevalent and major health problem, involving a complex integration of different organ systems, including the central nervous system (CNS). The CNS and the hypothalamus in particular are intricately involved in the pathogenesis of hypertension. In fact, evidence supports altered hypothalamic neuronal activity as a major factor contributing to increased sympathetic drive and increased blood pressure. Several mechanisms have been proposed to contribute to hypothalamic-driven sympathetic activity, including altered ion channel function. Ion channels are critical regulators of neuronal excitability and synaptic function in the brain and, thus, important for blood pressure homeostasis regulation. These include sodium channels, voltage-gated calcium channels, and potassium channels being some of them already identified in hypothalamic neurons. This brief review summarizes the hypothalamic ion channels that may be involved in hypertension, highlighting recent findings that suggest that hypothalamic ion channel modulation can affect the central control of blood pressure and, therefore, suggesting future development of interventional strategies designed to treat hypertension.
KeywordsHypothalamus Ion channels Hypertension Sympathetic nervous system Sodium channels Calcium channels Potassium channels
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Conflict of Interest
Dr. Rocha reports a grant from Portuguese Foundation for Science and Technology [2010–2013–FCT/PTDC/SAU-OSM/109081/2008]. The other authors declare no conflicts of interest relevant to this manuscript.
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This article does not contain any studies with human or animal subjects performed by any of the authors.
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- 2.• Hwang AY, Dietrich E, Pepine CJ, Smith SM. Resistant Hypertension: Mechanisms and Treatment. Current Hypertension Reports. 2017;19(7):56. This review article summarize the multiple mechanisms, including the sympathetic nervous system that play an important role in development of treatment-resistant hypertension. https://doi.org/10.1007/s11906-017-0754-x.CrossRefPubMedGoogle Scholar
- 3.Dibona GF. Sympathetic nervous system and hypertension. Hypertension 2013; 61(3), 556–560, https://doi.org/10.1161/HYPERTENSIONAHA.111.00633.
- 4.•• Geraldes V, Gonçalves-Rosa N, Liu B, Paton JF, Rocha I. Chronic depression of hypothalamic paraventricular neuronal activity produces sustained hypotension in hypertensive rats. Exp Physiol. 2014;99(1):89–100. The study shows, for the first time, that overexpression of an inwardly rectifying potassium channel in the PVN provided a long-term antihypertensive response in conscious spontaneously hypertensive rats, supporting this area as a therapeutic target for the chronic control of blood pressure in neurogenic hypertension. https://doi.org/10.1113/expphysiol.2013.074823.CrossRefPubMedGoogle Scholar
- 5.•• Sonner PM, Lee S, Ryu PD, Lee SY, Stern JE. Imbalanced K+ and Ca2+ subthreshold interactions contribute to increased hypothalamic presympathetic neuronal excitability in hypertensive rats. J Physiol. 2011;589(3):667–83. The interplay between potassium and calcium channels biophysical properties influences PVN-RVLM pathway activity which may contribute to the characteristic sympathoexcitation observed in hypertension. CrossRefPubMedGoogle Scholar
- 6.• Geraldes V, Goncalves-Rosa N, Tavares C, Paton JF & Rocha I. Reversing gene expression in cardiovascular target organs following chronic depression of the paraventricular nucleus of hypothalamus and rostral ventrolateral medulla in spontaneous hypertensive rats. Brain Res. 2016; 1646, 109–115. This study complements reference 4 by showing reverse remodelling in hypertensive target organs after genetic modification of cellular excitability at hypothalamic PVN. Google Scholar
- 7.• Li DP, Zhu LH, Pachuau J, Lee HA, Pan HL. mGluR5 upregulation increases excitability of hypothalamic presympathetic neurons through NMDA receptor trafficking in spontaneously hypertensive rats. J Neurosci. 2014;34(12):4309–17. The upregulation of mGluR5 in the PVN is contributes to the hyperactivity of PVN presympathetic neurons through PKC- and SNAP-25-mediated surface expression of NMDARs. CrossRefPubMedGoogle Scholar
- 9.•• Carmichael CY, Wainford RD. Hypothalamic signalling mechanisms in hypertension. Curr Hypertens Rep. 2015;17(5):39. This review highlights recent improvements in our understanding of signal transduction pathways within the hypothalamus that impact the aethiology and pathogenesis of hypertension CrossRefPubMedPubMedCentralGoogle Scholar
- 12.•• Zheng J & Trudeau MC (Eds.). Handbook of ion channels. CRC Press; 2015. This book provides a modern guide to the properties and functions of major families of ion channels, and presents powerful methods for modelling channelopathies and performing clinical trials for ion channel drugs. It also addresses ion channel regulation as well as its trafficking and distribution. Google Scholar
- 18.Curran J, Mohler PJ. Alternative paradigms for ion channelopathies: disorders of ion channel membrane trafficking and posttranslational modification. Annu Rev Physiol. 2015;77:505–24, 1. https://doi.org/10.1146/annurev-physiol-021014-071838.CrossRefPubMedGoogle Scholar
- 20.Carmay L, Todor D. "Chapter 10. Potassium Versus Sodium Selectivity in Monovalent Ion Channel Selectivity Filters". In Astrid, Sigel; Helmut, Sigel; Roland K.O., Sigel. The Alkali Metal Ions: Their Role in Life. Metal Ions in Life Sciences. 2016; 16. Springer. pp. 325–347..Google Scholar
- 23.Tanaka M, Cummins TR, Ishikawa K, Black JA, Ibata Y, Waxman SG. Molecular and functional remodelling of electrogenic membrane of hypothalamic neurons in response to changes in their input. Proc Natl Acad Sci. 1999;96(3):1088–93. https://doi.org/10.1073/pnas.96.3.1088.CrossRefPubMedPubMedCentralGoogle Scholar
- 27.Ciriello J. Central neural mechanisms in cardiovascular regulation (Vol. 2). Springer Science & Business Media; 2012.Google Scholar
- 34.•• Sun Y, Zhang JN, Zhao D, Wang QS, Gu YC, Ma HP, et al. Role of the epithelial sodium channel in salt-sensitive hypertension. Acta Pharmacologica Sinica. 2011;32(6):789. The role of ENaC and its genetic variants expressed in vascular endothelia and the central nervous system in the development of salt-sensitive hypertension is discussed being considered that ENaC altered activity may affect the vascular endothelium and sympathetic activity to ultimately influence blood pressure. CrossRefPubMedPubMedCentralGoogle Scholar
- 40.Gründer S, Chen X. Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int J Physiol, Pathophysiol Pharmacol. 2010;2(2):73–94.Google Scholar
- 42.Meng QY, Wang W, Chen XN, Xu TL, Zhou JN. Distribution of acid-sensing ion channel 3 in the rat hypothalamus. Neuroscience. 2009;159(3):1126–34. https://doi.org/10.1016/j.neuroscience.2009.01.069.CrossRefPubMedGoogle Scholar
- 44.Wu WN, Wu PF, Zhou J, Guan XL, Zhang Z, Yang YJ, et al. Orexin-A activates hypothalamic AMP-activated protein kinase signaling through a Ca2+−dependent mechanism involving voltage-gated L-type calcium channel. Mol Pharmacol. 2013;84(6):876–87. https://doi.org/10.1124/mol.113.086744.CrossRefPubMedGoogle Scholar
- 45.Lee S, Han TH, Sonner PM, Stern JE, Ryu PD, Lee SY. Molecular characterization of T-type Ca2+ channels responsible for low threshold spikes in hypothalamic paraventricular nucleus neurons. Neuroscience. 2008;155:1195–203, 4. https://doi.org/10.1016/j.neuroscience.2008.06.055.CrossRefPubMedGoogle Scholar
- 46.• Lu CJ, Hao G, Nikiforova N, Larsen HE, Liu K, Crabtree MJ, et al. CAPON modulates neuronal calcium handling and cardiac sympathetic neurotransmission during dysautonomia in hypertension. Hypertension. 2015;65:1288–97. This study demonstrate that neuronal calcium currents are increased in pre-hypertensive states and can be reduced at nitric oxide synthase level. CrossRefPubMedPubMedCentralGoogle Scholar
- 48.•• Larsen HE, Bardsley EN, Lefkimmiatis K, Paterson DJ. Dysregulation of neuronal Ca2+ channel linked to heightened sympathetic phenotype in prohypertensive states. J Neurosci. 2016;36(33):8562–73. Dysregulation at calcium channels levels may provide a trigger for sympatho-excitation in the prohypertensive state which may be reversed to normal levels through cGMP rescue CrossRefPubMedPubMedCentralGoogle Scholar
- 50.Anderson D, Engbers JD, Heath NC, Bartoletti TM, Mehaffey WH, Zamponi GW & Turner RW. The Cav3–Kv4 complex acts as a calcium sensor to maintain inhibitory charge transfer during extracellular calcium fluctuations. J Neurosci 2013; 33(18), 7811–7824, https://doi.org/10.1523/JNEUROSCI.5384-12.2013.
- 51.Engbers JD, Zamponi GW, and Turner RW. Modelling interactions between voltage-gated ca (2+) channels and KCa1.1 channels. Channels (Austin) 2013; 7:524–529, 6, DOI: 10.4161/chan.25867.Google Scholar
- 56.Bean AJ (Ed.). Protein trafficking in neurons. Academic Press. 2006.Google Scholar
- 57.Tao J, Lan Z, Wang Y, Hei H, Tian L, Pan W, ... & Peng W. Large-Conductance Calcium-Activated Potassium Channels in Glomerulus: From Cell Signal Integration to Disease. Frontiers in physiology. 2016; 7.Google Scholar
- 58.Zhang J, Yan J. Regulation of BK channels by auxiliary γ subunits. Front Physiol. 2014;5Google Scholar
- 60.• Contet C, Goulding SP, Kuljis DA, Barth AL. BK channels in the central nervous system. Int Rev Neurobiol. 2016;128:281–342. BK channels regulate the timing and duration of potassium influx depending on the cellular context exerting a neuroprotective role in several pathological conditions. https://doi.org/10.1016/bs.irn.2016.04.001.CrossRefPubMedPubMedCentralGoogle Scholar
- 61.Bhattarai Y, Fernandes R, Kadrofske MM, Lockwood LR, Galligan JJ, Xu H. Western blot analysis of BK channel β1-subunit expression should be interpreted cautiously when using commercially available antibodies. Physiological Reports. 2014;2(10)):e12189. https://doi.org/10.14814/phy2.12189.CrossRefPubMedPubMedCentralGoogle Scholar
- 62.• Wulff H, Castle NA, Pardo LA. Voltage-gated potassium channels as therapeutic drug targets. Nature reviews. Drug Discov. 2009;8(12):982. Voltage-gated potassium channels by regulating various physiological and pathophysiological processes may constitute pharmacological options to be tested in preclinical and clinical studies CrossRefGoogle Scholar
- 63.•• Pachuau J, Li DP, Chen SR, Lee HA, Pan HL. Protein kinase CK2 contributes to diminished small conductance Ca2+−activated K+ channel activity of hypothalamic pre-sympathetic neurons in hypertension. J Neurochem. 2014;130(5):657–67. Reduced SK channel activity plays a role in hyperactivity of hypothalamic pre-sympathetic neurons in hypertension CrossRefPubMedPubMedCentralGoogle Scholar
- 65.• Gui L, LaGrange LP, Larson RA, Gu M, Zhu J, Chen QH. Role of small conductance calcium-activated potassium channels expressed in PVN in regulating sympathetic nerve activity and arterial blood pressure in rats. Am J Phys Regul Integr Comp Phys. 2012;303(3):R301–10. SK channels expressed in the PVN play an important role in the regulation of sympathetic outflow and cardiovascular function. https://doi.org/10.1152/ajpregu.00114.2012.Google Scholar
- 67.Chen QH, Andrade MA, Calderon AS, Toney GM. Hypertension induced by angiotensin II and a high salt diet involves reduced SK current and increased excitability of RVLM projecting PVN neurons. J Neurophysiol. 2010;104:2329–37, 5. https://doi.org/10.1152/jn.01013.2009.CrossRefPubMedPubMedCentralGoogle Scholar
- 69.Cheng Z, Lin M, Toney GM, Chen Q. Small-conductance Ca2+−activated K+ (SK) channels regulate pre-sympathetic neurons in the hypothalamic paraventricular nucleus (PVN) and parasympathetic cardiomotor neurons (CMN) in the nucleus ambiguus (NA): pathological changes. FASEB J. 2017;31(1 Supplement):718–5.Google Scholar
- 71.• Ye ZY, Li DP, Li L, Pan HL. Protein kinase CK2 increases glutamatergic input in the hypothalamus and sympathetic vasomotor tone in hypertension. J Neurosci. 2011;31(22):8271–9. Hypothalamic CK2 in the PVN is increased and contributes to sympathetic vasomotor tone regulation in hypertension. CrossRefPubMedPubMedCentralGoogle Scholar
- 73.Sohn JW. Ion channels in the central regulation of energy and glucose homeostasis. Front Neurosci 2013; 7, https://doi.org/10.3389/fnins.2013.00085.
- 74.Doherty FC, Schaack JB, Sladek CD. Comparison of the efficacy of four viral vectors for transducing hypothalamic magnocellular neurosecretory neurons in the rat supraoptic nucleus. J Neurosci Methods 2011; 197, pp. 238–248, 2, https://doi.org/10.1016/j.jneumeth.2011.02.026.
- 76.Okada M, Matsuda H. Chronic lentiviral expression of inwardly rectifying K+ channels (Kir2.1) reduces neuronal activity and downregulates voltage-gated potassium currents in hippocampus. Neuroscience. 2008;156(2):289–97. https://doi.org/10.1016/j.neuroscience.2008.07.038.CrossRefPubMedGoogle Scholar
- 80.Johns DC, Marx R, Mains RE, O'Rourke B, Marban E. Inducible genetic suppression of neuronal excitability. J Neurosci 1999; 19 pp. 1691–1697, 5.Google Scholar
- 81.Ehrengruber MU, Doupnik CA, Xu Y, Garvey J, Jasek MC, Lester HA, et al. Activation of heteromeric G protein-gated inward rectifier K+ channels overexpressed by adenovirus gene transfer inhibits the excitability of hippocampal neurons. Proc Natl Acad Sci. 1997;94(13):7070–5. https://doi.org/10.1073/pnas.94.13.7070.CrossRefPubMedPubMedCentralGoogle Scholar
- 89.• Talley EM, Solórzano G, Lei Q, Kim D, Bayliss DA. CNS distribution of members of the two-pore-domain (KCNK) potassium channel family. J Neurosci. 2001;21(19):7491–505. In this study, authors report on the CNS distribution in the rat and mouse of mRNA encoding seven two-pore-domain K(+) channel family members. High levels of TASK-3, TASK-1 and TREK-1 were found in hypothalamic nuclei. PubMedGoogle Scholar
- 91.Coutinho E & Vincent A. Central nervous system neuronal surface antibodies. Autoantibodies: Third Edition 2013; 595–603.Google Scholar
- 92.Triggle DJ, Gopalakrishnan M, Rampe D & Zheng W. Voltage-gated ion channels as drug targets, Wiley-VCH; volume 29. 2006, https://doi.org/10.1002/3527608141.
- 93.Grizel AV, Glukhov GS & Sokolova OS. Mechanisms of activation of voltage-gated potassium channels. Acta Naturae (англоязычная версия). 2014; 6(4 (23)).Google Scholar
- 95.• Sonner PM, Stern JE. Functional role of A-type potassium currents in rat presympathetic PVN neurones. J Physiol. 2007;582(3):1219–38. Potassium currents PVN-RVLM neurones actively modulate their action potential waveform and firing activity which gives support to potassium currents as an important intrinsic mechanism controlling neuronal excitability in PVN-RVLM pathway CrossRefPubMedPubMedCentralGoogle Scholar
- 97.Lee SK, Lee S, Shin SY, Ryu PD, Lee SY. Single cell analysis of voltage-gated potassium channels that determines neuronal types of rat hypothalamic paraventricular nucleus neurons. Neuroscience. 2012;205:49–62. https://doi.org/10.1016/j.neuroscience.2011.12.031.CrossRefPubMedGoogle Scholar
- 98.Alonso G & Widmer H. Clustering of KV4. 2 potassium channels in postsynaptic membrane of rat supraoptic neurons: an ultrastructural study. Neuroscience 1997; 77(3), 617–621.Google Scholar
- 99.• Kline DD. Tuning excitability of the hypothalamus via glutamate and potassium channel coupling. J Physiol. 2017; 15;595(14):4583–4584. A strong rationale to deeper investigate the role of the hypothalamic channels coupling is provided. The review illustrates a putative mechanism driving to hypertension in the hypothalamic supraoptic nucleus. Google Scholar
- 101.• Sonner PM, Filosa JA, Stern JE. Diminished A-type potassium current and altered firing properties in presympathetic PVN neurones in renovascular hypertensive rats. J Physiol. 2008;586:1605–22. This study shows that down-regulation potassium channels contributes to increased hypothalamic neuronal excitability in renovascular hypertension. CrossRefPubMedPubMedCentralGoogle Scholar
- 102.Naskar K, Stern JE. A functional coupling between extrasynaptic NMDA receptors and A-type K+ channels under astrocyte control regulates hypothalamic neurosecretory neuronal activity. J Physiol. 2014;592(Pt 13):2813–27. https://doi.org/10.1113/jphysiol.2014.270793.CrossRefPubMedPubMedCentralGoogle Scholar
- 103.Kline DD. Tuning excitability of the hypothalamus via glutamate and potassium channel coupling. J Physiol. 2017; 15;595(14):4583–4584.Google Scholar