Skip to main content
SpringerLink
Log in

Potassium Channels: A Potential Therapeutic Target for Parkinson’s Disease

  • Review
  • Published:
Neuroscience Bulletin Aims and scope Submit manuscript

Abstract

The pathogenesis of the second major neurodegenerative disorder, Parkinson’s disease (PD), is closely associated with the dysfunction of potassium (K+) channels. Therefore, PD is also considered to be an ion channel disease or neuronal channelopathy. Mounting evidence has shown that K+ channels play crucial roles in the regulations of neurotransmitter release, neuronal excitability, and cell volume. Inhibition of K+ channels enhances the spontaneous firing frequency of nigral dopamine (DA) neurons, induces a transition from tonic firing to burst discharge, and promotes the release of DA in the striatum. Recently, three K+ channels have been identified to protect DA neurons and to improve the motor and non-motor symptoms in PD animal models: small conductance (SK) channels, A-type K+ channels, and KV7/KCNQ channels. In this review, we summarize the physiological and pharmacological effects of the three K+ channels. We also describe in detail the laboratory investigations regarding K+ channels as a potential therapeutic target for PD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Przedborski S. The two-century journey of Parkinson disease research. Nat Rev Neurosci 2017, 18: 251–259.

    Article  CAS  PubMed  Google Scholar 

  2. Pires AO, Teixeira FG, Mendes-Pinheiro B, Serra SC, Sousa N, Salgado AJ. Old and new challenges in Parkinson’s disease therapeutics. Prog Neurobiol 2017, 156: 69–89.

    Article  CAS  PubMed  Google Scholar 

  3. Lawson K, McKay NG. Modulation of potassium channels as a therapeutic approach. Curr Pharm Des 2006, 12: 459–470.

    Article  CAS  PubMed  Google Scholar 

  4. Doyle DA, Cabral JM, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 1998, 280: 69–77.

    Article  CAS  PubMed  Google Scholar 

  5. Wang Y, Yang PL, Tang JF, Lin JF, Cai XH, Wang XT, et al. Potassium channels: possible new therapeutic targets in Parkinson’s disease. Med Hypotheses 2008, 71: 546–550.

    Article  CAS  PubMed  Google Scholar 

  6. Du X, Xu H, Shi L, Jiang Z, Song N, Jiang H, et al. Activation of ATP-sensitive potassium channels enhances DMT1-mediated iron uptake in SK-N-SH cells in vitro. Sci Rep 2016, 6: 33674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Martel P, Leo D, Fulton S, Berard M, Trudeau LE. Role of Kv1 potassium channels in regulating dopamine release and presynaptic D2 receptor function. PLoS One 2011, 6: e20402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Lüscher C, Slesinger PA. Emerging roles for G protein-gated inwardly rectifying potassium (GIRK) channels in health and disease. Nat Rev Neurosci 2010, 11: 301–315.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Mayfield J, Blednov YA, Harris RA. Behavioral and genetic evidence for GIRK channels in the CNS: role in physiology, pathophysiology, and drug addiction. Int Rev Neurobiol 2015, 123: 279–313.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Duda J, Pötschke C, Liss B. Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson’s disease. J Neurochem 2016, 139: 156–178.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Du XX, Qin K, Jiao Q, Xie JX, Jiang H. Advances in the association of ATP-sensitive potassium channels and Parkinson’s disease. Acta Physiol Sin 2016, 68: 644–648.

    PubMed  Google Scholar 

  12. Maurice N, Deltheil T, Melon C, Degos B, Mourre C, Amalric M, et al. Bee venom alleviates motor deficits and modulates the transfer of cortical information through the basal ganglia in rat models of Parkinson’s disease. PLoS One 2015, 10: e0142838.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Aidi-Knani S, Regaya I, Amalric M, Mourre C. Kv4 channel blockade reduces motor and neuropsychiatric symptoms in rodent models of Parkinson’s disease. Behav Pharmacol 2015, 26: 91–100.

    Article  CAS  PubMed  Google Scholar 

  14. Pérez-Ramírez MB, Laville A, Tapia D, Duhne M, Lara-González E, Bargas J, et al. KV7 channels regulate firing during synaptic integration in GABAergic striatal neurons. Neural Plast 2015, 2015: 472676.

  15. Sørensen US, Strøbæk D, Christophersen P, Hougaard C, Jensen ML, Nielsen EØ, et al. Synthesis and structure−activity relationship studies of 2-(N-substituted)-aminobenzimidazoles as potent negative gating modulators of small conductance Ca2+-activated K+ channels. J Med Chem 2008, 51: 7625–7634.

    Article  PubMed  Google Scholar 

  16. Lam J, Coleman N, Garing ALA, Wulff H. The therapeutic potential of small-conductance KCa2 channels in neurodegenerative and psychiatric diseases. Expert Opin Ther Targets 2013, 17: 1203–1220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bond CT, Herson PS, Strassmaier T, Hammond R, Stackman R, Maylie J, et al. Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J Neurosci 2004, 24: 5301–5306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Deignan J, Luján R, Bond C, Riegel A, Watanabe M, Williams JT, et al. SK2 and SK3 expression differentially affect firing frequency and precision in dopamine neurons. Neuroscience 2012, 217: 67–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Hallworth NE, Wilson CJ, Bevan MD. Apamin-sensitive small conductance calcium-activated potassium channels, through their selective coupling to voltage-gated calcium channels, are critical determinants of the precision, pace, and pattern of action potential generation in rat subthalamic nucleus neurons in vitro. J Neurosci 2003, 23: 7525–7542.

    CAS  PubMed  Google Scholar 

  20. Wolfart J, Neuhoff H, Franz O, Roeper J. Differential expression of the small-conductance, calcium-activated potassium channel SK3 is critical for pacemaker control in dopaminergic midbrain neurons. J Neurosci 2001, 21: 3443–3456.

    CAS  PubMed  Google Scholar 

  21. Chen L, Deltheil T, Turle-Lorenzo N, Liberge M, Rosier C, Watabe I, et al. SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats. Int J Neuropsychopharmacol 2014, 17: 1295–1306.

    Article  CAS  PubMed  Google Scholar 

  22. Waroux O, Massotte L, Alleva L, Graulich A, Thomas E, Liégeois JF, et al. SK channels control the firing pattern of midbrain dopaminergic neurons in vivo. Eur J Neurosci 2005, 22: 3111–3121.

    Article  PubMed  Google Scholar 

  23. Liegeois J, Mercier F, Graulich A, Graulich-Lorge F, Scuvée-Moreau J, Seutin V. Modulation of small conductance calcium-activated potassium (SK) channels: a new challenge in medicinal chemistry. Curr Med Chem 2003, 10: 625–647.

    Article  CAS  PubMed  Google Scholar 

  24. Adelman JP, Maylie J, Sah P. Small-conductance Ca2+-activated K+ channels: form and function. Annu Rev Physiol 2012, 74: 245–269.

    Article  CAS  PubMed  Google Scholar 

  25. Liu XK, Wang G, Chen SD. Modulation of the activity of dopaminergic neurons by SK channels: a potential target for the treatment of Parkinson’s disease? Neurosci Bull 2010, 26: 265–271.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Sarpal D, Koenig JI, Adelman JP, Brady D, Prendeville LC, Shepard PD. Regional distribution of SK3 mRNA‐containing neurons in the adult and adolescent rat ventral midbrain and their relationship to dopamine‐containing cells. Synapse 2004, 53: 104–113.

    Article  CAS  PubMed  Google Scholar 

  27. Mourre C, Manrique C, Camon J, Aidi-Knani S, Deltheil T, Turle-Lorenzo N, et al. Changes in SK channel expression in the basal ganglia after partial nigrostriatal dopamine lesions in rats: Functional consequences. Neuropharmacology 2017, 113: 519–532.

    Article  CAS  PubMed  Google Scholar 

  28. Doo A-R, Kim S-T, Kim S-N, Moon W, Yin CS, Chae Y, et al. Neuroprotective effects of bee venom pharmaceutical acupuncture in acute 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine-induced mouse model of Parkinson’s disease. Neurol Res 2010, 32: 88–91.

    Article  PubMed  Google Scholar 

  29. Alvarez-Fischer D, Noelker C, Vulinović F, Grünewald A, Chevarin C, Klein C, et al. Bee venom and its component apamin as neuroprotective agents in a Parkinson disease mouse model. PLoS One 2013, 8: e61700.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kim J-I, Yang EJ, Lee MS, Kim Y-S, Huh Y, Cho I-H, et al. Bee venom reduces neuroinflammation in the MPTP-induced model of Parkinson’s disease. Int J Neurosci 2011, 121: 209–217.

    Article  CAS  PubMed  Google Scholar 

  31. Hartmann A, Müllner J, Meier N, Hesekamp H, Van Meerbeeck P, Habert M-O, et al. Bee venom for the treatment of Parkinson disease–a randomized controlled clinical trial. PLoS One 2016, 11: e0158235.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Salthun-Lassalle B, Hirsch EC, Wolfart J, Ruberg M, Michel PP. Rescue of mesencephalic dopaminergic neurons in culture by low-level stimulation of voltage-gated sodium channels. J Neurosci 2004, 24: 5922–5930.

    Article  CAS  PubMed  Google Scholar 

  33. Wolfart J, Roeper J. Selective coupling of T-type calcium channels to SK potassium channels prevents intrinsic bursting in dopaminergic midbrain neurons. J Neurosci 2002, 22: 3404–3413.

    CAS  PubMed  Google Scholar 

  34. Aumann T, Gantois I, Egan K, Vais A, Tomas D, Drago J, et al. SK channel function regulates the dopamine phenotype of neurons in the substantia nigra pars compacta. Exp Neurol 2008, 213: 419–430.

    Article  CAS  PubMed  Google Scholar 

  35. Ji H, Shepard P. SK Ca2+-activated K+ channel ligands alter the firing pattern of dopamine-containing neurons in vivo. Neuroscience 2006, 140: 623–633.

    Article  CAS  PubMed  Google Scholar 

  36. Wang Y, Qu L, Wang X-L, Gao L, Li Z-Z, Gao G-D, et al. Firing pattern modulation through SK channel current increase underlies neuronal survival in an organotypic slice model of Parkinson’s disease. Mol Neurobiol 2015, 51: 424–436.

    Article  CAS  PubMed  Google Scholar 

  37. Dolga A, De Andrade A, Meissner L, Knaus H, Höllerhage M, Christophersen P, et al. Subcellular expression and neuroprotective effects of SK channels in human dopaminergic neurons. Cell Death Dis 2014, 5: e999.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gold M. Modulation mikroglialer Zellen in der Alzheimer-assoziierten Neuroinflammation (http://dx.doi.org/10.17192/z2013.0643). Philipps-Universität Marburg.

  39. Dolga AM, Culmsee C. Protective roles for potassium SK/KCa2 channels in microglia and neurons. Front Pharmacol 2012, 3: 196.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zhang Y, Dawson VL, Dawson TM. Oxidative stress and genetics in the pathogenesis of Parkinson’s disease. Neurobiol Dis 2000, 7: 240–250.

    Article  CAS  PubMed  Google Scholar 

  41. Sapolsky RM. Cellular defenses against excitotoxic insults. J Neurochem 2001, 76: 1601–1611.

    Article  CAS  PubMed  Google Scholar 

  42. Birnbaum SG, Varga AW, Yuan LL, Anderson AE, Sweatt JD, Schrader LA. Structure and function of Kv4-family transient potassium channels. Physiol Rev 2004, 84: 803–833.

    Article  CAS  PubMed  Google Scholar 

  43. Serôdio P, Rudy B. Differential expression of Kv4 K+ channel subunits mediating subthreshold transient K+ (A-type) currents in rat brain. J Neurophysiol 1998, 79: 1081–1091.

    Article  PubMed  Google Scholar 

  44. Subramaniam M, Althof D, Gispert S, Schwenk J, Auburger G, Kulik A, et al. Mutant α-synuclein enhances firing frequencies in dopamine substantia nigra neurons by oxidative impairment of A-type potassium channels. J Neurosci 2014, 34: 13586–13599.

    Article  PubMed  Google Scholar 

  45. Dragicevic E, Schiemann J, Liss B. Dopamine midbrain neurons in health and Parkinson’s disease: emerging roles of voltage-gated calcium channels and ATP-sensitive potassium channels. Neuroscience 2015, 284: 798–814.

    Article  CAS  PubMed  Google Scholar 

  46. Liss B, Franz O, Sewing S, Bruns R, Neuhoff H, Roeper J. Tuning pacemaker frequency of individual dopaminergic neurons by Kv4. 3L and KChip3. 1 transcription. EMBO J 2001, 20: 5715–5724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Dufour MA, Woodhouse A, Goaillard JM. Somatodendritic ion channel expression in substantia nigra pars compacta dopaminergic neurons across postnatal development. J Neurosci Res 2014, 92: 981–999.

    Article  CAS  PubMed  Google Scholar 

  48. Haghdoost-Yazdi H, Faraji A, Fraidouni N, Movahedi M, Hadibeygi E, Vaezi F. Significant effects of 4-aminopyridine and tetraethylammonium in the treatment of 6-hydroxydopamine-induced Parkinson’s disease. Behav Brain Res 2011, 223: 70–74.

    Article  CAS  PubMed  Google Scholar 

  49. Sun W, Smith D, Fu Y, Cheng JX, Bryn S, Borgens R, et al. Novel potassium channel blocker, 4-AP-3-MeOH, inhibits fast potassium channels and restores axonal conduction in injured guinea pig spinal cord white matter. J Neurophysiol 2010, 103: 469–478.

    Article  CAS  PubMed  Google Scholar 

  50. Tkatch T, Baranauskas G, Surmeier DJ. Kv4. 2 mRNA abundance and A-type K+ current amplitude are linearly related in basal ganglia and basal forebrain neurons. J Neurosci 2000, 20: 579–588.

    CAS  PubMed  Google Scholar 

  51. Falk T, Zhang S, Erbe EL, Sherman SJ. Neurochemical and electrophysiological characteristics of rat striatal neurons in primary culture. J Comp Neurol 2006, 494: 275–289.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Day M, Wokosin D, Plotkin JL, Tian X, Surmeier DJ. Differential excitability and modulation of striatal medium spiny neuron dendrites. J Neurosci 2008, 28: 11603–11614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Maffie JK, Dvoretskova E, Bougis PE, Martin‐Eauclaire MF, Rudy B. Dipeptidyl-peptidase-like-proteins confer high sensitivity to the scorpion toxin AmmTX3 to Kv4‐mediated A‐type K+ channels. J Physiol 2013, 591: 2419–2427.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Vacher H, Alami M, Crest M, Possani LD, Bougis PE, Martin‐Eauclaire MF. Expanding the scorpion toxin α‐KTX 15 family with AmmTX3 from Androctonus mauretanicus. FEBS J 2002, 269: 6037–6041.

    CAS  Google Scholar 

  55. Aidi-Knani S, Regaya I, Amalric M, Mourre C. Kv4 channel blockade reduces motor and neuropsychiatric symptoms in rodent models of Parkinson’s disease. Behav Pharmacol 2015, 26: 91–100.

    Article  CAS  PubMed  Google Scholar 

  56. Haghdoost-Yazdi H, Piri H, Najafipour R, Faraji A, Fraidouni N, Dargahi T, et al. Blockade of fast A-type and TEA-sensitive potassium channels provide an antiparkinsonian effect in a 6-OHDA animal model. Neurosciences (Riyadh) 2017, 22: 44.

    Article  Google Scholar 

  57. Taherian R, Ahmadi MA. 4-aminopyridine decreases MPTP-induced behavioral disturbances in animal model of Parkinson’s disease. Int Clin Neurosci J 2016, 2: 142–146.

    Google Scholar 

  58. Yang F, Feng L, Zheng F, Johnson SW, Du J, Shen L, et al. GDNF acutely modulates excitability and A-type K+ channels in midbrain dopaminergic neurons. Nat Neurosci 2001, 4: 1071–1078.

    Article  CAS  PubMed  Google Scholar 

  59. Hansen HH, Ebbesen C, Mathiesen C, Weikop P, Rønn LC, Waroux O, et al. The KCNQ channel opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat. J Pharmacol Exp Ther 2006, 318: 1006–1019.

    Article  CAS  PubMed  Google Scholar 

  60. Cooper EC, Harrington E, Jan YN, Jan LY. M channel KCNQ2 subunits are localized to key sites for control of neuronal network oscillations and synchronization in mouse brain. J Neurosci 2001, 21: 9529–9540.

    CAS  PubMed  Google Scholar 

  61. Weber YG, Geiger J, Kämpchen K, Landwehrmeyer B, Sommer C, Lerche H. Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain. Brain Res 2006, 1077: 1–6.

    Article  CAS  PubMed  Google Scholar 

  62. Martire M, D’Amico M, Panza E, Miceli F, Viggiano D, Lavergata F, et al. Involvement of KCNQ2 subunits in [3H] dopamine release triggered by depolarization and pre‐synaptic muscarinic receptor activation from rat striatal synaptosomes. J Neurochem 2007, 102: 179–193.

    Article  CAS  PubMed  Google Scholar 

  63. Saganich M, Machado E, Rudy B. Differential expression of genes encoding subthreshold-operating voltage-gated K+ channels in brain. J Neurosci 2001, 21: 4609–4624.

    CAS  PubMed  Google Scholar 

  64. Shen W, Hamilton SE, Nathanson NM, Surmeier DJ. Cholinergic suppression of KCNQ channel currents enhances excitability of striatal medium spiny neurons. J Neurosci 2005, 25: 7449–7458.

    Article  CAS  PubMed  Google Scholar 

  65. Peretz A, Sheinin A, Yue C, Degani-Katzav N, Gibor G, Nachman R, et al. Pre-and postsynaptic activation of M-channels by a novel opener dampens neuronal firing and transmitter release. J Neurophysiol 2007, 97: 283–295.

    Article  CAS  PubMed  Google Scholar 

  66. Hansen HH, Weikop P, Mikkelsen MD, Rode F, Mikkelsen JD. The pan-Kv7 (KCNQ) channel opener retigabine inhibits striatal excitability by direct action on striatal neurons in vivo. Basic Clin Pharmacol Toxicol 2017, 120: 46–51.

    Article  CAS  PubMed  Google Scholar 

  67. Shi L, Bian X, Qu Z, Ma Z, Zhou Y, Wang K, et al. Peptide hormone ghrelin enhances neuronal excitability by inhibition of Kv7/KCNQ channels. Nat Commun 2013, 4: 1435.

    Article  PubMed  Google Scholar 

  68. Drion G, Bonjean M, Waroux O, Scuvée‐Moreau J, Liégeois JF, Sejnowski TJ, et al. M‐type channels selectively control bursting in rat dopaminergic neurons. Eur J Neurosci 2010, 31: 827–835.

    Article  PubMed  PubMed Central  Google Scholar 

  69. Sander S, Lemm C, Lange N, Hamann M, Richter A. Retigabine, a KV 7 (KCNQ) potassium channel opener, attenuates l-DOPA-induced dyskinesias in 6-OHDA-lesioned rats. Neuropharmacology 2012, 62: 1052–1061.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This review was supported by the National Natural Science Foundation of China (31671054 and 81430024), the Postdoctoral Science Foundation of China (2017M610412), and the Bureau of Science and Technology of Qingdao Municipality, China (17-1-1-44-jch).

Author information

Author notes

  1. Xiaoyan Chen and Bao Xue have contributed equally to this review.

Authors and Affiliations

  1. Collaborative Innovation Center for Brain Science, Department of Physiology, Shandong Provincial Collaborative Innovation Center for Neurodegenerative Disorders, Key Laboratory of Pathogenesis and Prevention of Neurological Disorders, Medical College of Qingdao University, Qingdao, 266071, China

    Xiaoyan Chen, Bao Xue, Jun Wang, Haixia Liu, Limin Shi & Junxia Xie

Authors
  1. Xiaoyan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bao Xue
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Haixia Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Limin Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Junxia Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Limin Shi or Junxia Xie.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, X., Xue, B., Wang, J. et al. Potassium Channels: A Potential Therapeutic Target for Parkinson’s Disease. Neurosci. Bull. 34, 341–348 (2018). https://doi.org/10.1007/s12264-017-0177-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12264-017-0177-3

Keywords

Search

Navigation