Skip to main content
Log in

New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels

  • Published:
Current Neurology and Neuroscience Reports Aims and scope Submit manuscript

Abstract

Many currently prescribed antiepileptic drugs (AEDs) act via voltage-gated sodium channels, through effects on γ-aminobutyric acid-mediated inhibition, or via voltage-gated calcium channels. Some newer AEDs do not act via these traditional mechanisms. The molecular targets for several of these nontraditional AEDs have been defined using cellular electrophysiology and molecular approaches. Here, we describe three of these targets: α2δ, auxiliary subunits of voltage-gated calcium channels through which the gabapentinoids gabapentin and pregabalin exert their anticonvulsant and analgesic actions; SV2A, a ubiquitous synaptic vesicle glycoprotein that may prepare vesicles for fusion and serves as the target for levetiracetam and its analog brivaracetam (which is currently in late-stage clinical development); and Kv7/KCNQ/M potassium channels that mediate the M-current, which acts a brake on repetitive firing and burst generation and serves as the target for the investigational AEDs retigabine and ICA-105665. Functionally, all of the new targets modulate neurotransmitter output at synapses, focusing attention on presynaptic terminals as critical sites of action for AEDs.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Rogawski MA, Löscher W: The neurobiology of antiepileptic drugs. Nature Rev Neurosci 2004, 5:553–564.

    Article  CAS  Google Scholar 

  2. Rogawski MA, Porter RJ: Antiepileptic drugs: pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol Rev 1990, 42:223–286.

    PubMed  CAS  Google Scholar 

  3. Gee NS, Brown JP, Dissanayake VU, et al.: The novel anticonvulsant drug, gabapentin (Neurontin) binds to the α2δ subunit of a calcium channel. J Biol Chem 1996, 271:5768–5776.

    Article  PubMed  CAS  Google Scholar 

  4. Rogawski MA: Molecular targets versus models for new antiepileptic drug discovery. Epilepsy Res 2006, 68:22–28.

    Article  PubMed  Google Scholar 

  5. Meldrum BS, Rogawski MA: Molecular targets for antiepileptic drug development. Neurotherapeutics 2007, 4:18–61.

    Article  PubMed  CAS  Google Scholar 

  6. Bryans JS, Wustrow DJ: 3-Substituted GABA analogs with central nervous system activity: a review. Med Res Rev 1999, 19:149–177.

    Article  PubMed  CAS  Google Scholar 

  7. Suman-Chauhan N, Webdale L, Hill DR, Woodruff GN: Characterisation of [3H]gabapentin binding to a novel site in rat brain: homogenate binding studies. Eur J Pharmacol 1993, 244:293–301.

    Article  PubMed  CAS  Google Scholar 

  8. Marais E, Klugbauer N, Hofmann F: Calcium channel α2δ subunits—structure and gabapentin binding. Mol Pharmacol 2001, 59:1243–1248.

    PubMed  CAS  Google Scholar 

  9. Qin N, Yagel S, Momplaisir ML, et al.: Molecular cloning and characterization of the human voltage-gated calcium channel α2δ-4 subunit. Mol Pharmacol 2002, 62:485–496.

    Article  PubMed  CAS  Google Scholar 

  10. Brown JP, Gee NS: Cloning and deletion mutagenesis of the α2δ calcium channel subunit from porcine cerebral cortex. Expression of a soluble form of the protein that retains [3H]gabapentin binding activity. J Biol Chem 1998, 273:25458–25465.

    Article  PubMed  CAS  Google Scholar 

  11. Wang M, Offord J, Oxender DL, Su TZ: Structural requirement of the calcium-channel subunit α2δ for gabapentin binding. Biochem J 1999, 342(Pt 2):313–320.

    Article  PubMed  CAS  Google Scholar 

  12. Field MJ, Cox PJ, Stott E, et al.: Identification of the α2δ subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc Natl Acad Sci U S A 2006, 103:17537–17542.

    Article  PubMed  CAS  Google Scholar 

  13. Bian F, Li Z, Offord J, et al.: Calcium channel α2δ type 1 subunit is the major binding protein for pregabalin in neocortex, hippocampus, amygdala, and spinal cord: an ex vivo autoradiographic study in α2δ type 1 genetically modified mice. Brain Res 2006, 1075:68–80.

    Article  PubMed  CAS  Google Scholar 

  14. Bryans JS, Davies N, Gee NS, et al.: Identification of novel ligands for the gabapentin binding site on the α2δ subunit of a calcium channel and their evaluation as anticonvulsant agents. J Med Chem 1998, 41:1838–1845.

    Article  PubMed  CAS  Google Scholar 

  15. Belliotti TR, Capiris T, Ekhato IV, et al.: Structure-activity relationships of pregabalin and analogues that target the α2δ protein. J Med Chem 2005, 48:2294–2307.

    Article  PubMed  CAS  Google Scholar 

  16. Barclay J, Balaguero N, Mione M, et al.: Ducky mouse phenotype of epilepsy and ataxia is associated with mutations in the Cacna2d2 gene and decreased calcium channel current in cerebellar Purkinje cells. J Neurosci 2001, 21:6095–6104.

    PubMed  CAS  Google Scholar 

  17. Brill J, Klocke R, Paul D, et al.: entla, a novel epileptic and ataxic Cacna2d2 mutant of the mouse. J Biol Chem 2004, 279:7322–7330.

    Article  PubMed  CAS  Google Scholar 

  18. Ivanov SV, Ward JM, Tessarollo L, et al.: Cerebellar ataxia, seizures, premature death, and cardiac abnormalities in mice with targeted disruption of the Cacna2d2 gene. Am J Pathol 2004, 165:1007–1018.

    PubMed  CAS  Google Scholar 

  19. Cunningham MO, Woodhall GL, Thompson SE, et al.: Dual effects of gabapentin and pregabalin on glutamate release at rat entorhinal synapses in vitro. Eur J Neurosci 2004, 20:1566–1576.

    Article  PubMed  Google Scholar 

  20. Micheva KD, Taylor CP, Smith SJ: Pregabalin reduces the release of synaptic vesicles from cultured hippocampal neurons. Mol Pharmacol 2006, 70:467–476.

    Article  PubMed  CAS  Google Scholar 

  21. van Hooft JA, Dougherty JJ, Endeman D, et al.: Gabapentin inhibits presynaptic Ca2+ influx and synaptic transmission in rat hippocampus and neocortex. Eur J Pharmacol 2002, 449:221–228.

    Article  PubMed  Google Scholar 

  22. Fink K, Dooley DJ, Meder WP, et al.: Inhibition of neuronal Ca2+ influx by gabapentin and pregabalin in the human neocortex. Neuropharmacology 2002, 42:229–236.

    Article  PubMed  CAS  Google Scholar 

  23. Dooley DJ, Mieske CA, Borosky SA: Inhibition of K+-evoked glutamate release from rat neocortical and hippocampal slices by gabapentin. Neurosci Lett 2000, 280:107–110.

    Article  PubMed  CAS  Google Scholar 

  24. Dooley DJ, Taylor CP, Donevan S, Feltner D: Ca2+ channel α2δ ligands: novel modulators of neurotransmission. Trends Pharmacol Sci 2007, 28:75–82.

    Article  PubMed  CAS  Google Scholar 

  25. Davies A, Hendrich J, Van Minh AT, et al.: Functional biology of the α2δ subunits of voltage-gated calcium channels. Trends Pharmacol Sci 2007, 28:220–228.

    Article  PubMed  CAS  Google Scholar 

  26. Hendrich J, Van Minh AT, Heblich F, et al.: Pharmacological disruption of calcium channel trafficking by the α2δ ligand gabapentin. Proc Natl Acad Sci U S A 2008, 105:3628–3633.

    Article  PubMed  CAS  Google Scholar 

  27. Dalby NO, Nielsen EB: Comparison of the preclinical anticonvulsant profiles of tiagabine, lamotrigine, gabapentin and vigabatrin. Epilepsy Res 1997, 28:63–72.

    Article  PubMed  CAS  Google Scholar 

  28. Löscher W, Reissmüller E, Ebert U: Anticonvulsant efficacy of gabapentin and levetiracetam in phenytoin-resistant kindled rats. Epilepsy Res 2000, 40:63–77.

    Article  PubMed  Google Scholar 

  29. Mandhane SN, Avaula K, Rajamannar T: Timed pentylenetetrazol infusion test: a comparative analysis with s.c.PTZ and MES models of anticonvulsant screening in mice. Seizure 2007, 16:636–644.

    Article  PubMed  Google Scholar 

  30. Bajjalieh SM, Peterson K, Linial M, Scheller RH: Brain contains two forms of synaptic vesicle protein 2. Proc Natl Acad Sci U S A 1993, 90:2150–2154.

    Article  PubMed  CAS  Google Scholar 

  31. Brose N, Rosenmund C: SV2: SVeeping up excess Ca2+ or tranSVorming presynaptic Ca2+ sensors? Neuron 1999, 24:766–768.

    Article  PubMed  CAS  Google Scholar 

  32. Custer KL, Austin NS, Sullivan JM, Bajjalieh SM: Synaptic vesicle protein 2 enhances release probability at quiescent synapses. J Neurosci 2006, 26:1303–1313.

    Article  PubMed  CAS  Google Scholar 

  33. Crowder KM, Gunther JM, Jones TA, et al.: Abnormal neurotransmission in mice lacking synaptic vesicle protein 2A (SV2A). Proc Natl Acad Sci U S A 1999, 96:15268–15273.

    Article  PubMed  CAS  Google Scholar 

  34. Leclercq K, Kaminski R, Dassesse D, et al.: Seizure susceptibility of SV2A heterozygous mice in models of temporal lobe epilepsy. Program No. 492.17. 2007 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience. Online.

    Google Scholar 

  35. Dong M, Yeh F, Tepp WH, et al.: SV2 is the protein receptor for botulinum neurotoxin A. Science 2006, 312:592–596.

    Article  PubMed  CAS  Google Scholar 

  36. Noyer M, Gillard M, Matagne A, et al.: The novel antiepileptic drug levetiracetam (ucb L059) appears to act via a specific binding site in CNS membranes. Eur J Pharmacol 1995, 286:137–146.

    Article  PubMed  CAS  Google Scholar 

  37. Fuks B, Gillard M, Michel P, et al.: Localization and photoaffinity labelling of the levetiracetam binding site in rat brain and certain cell lines. Eur J Pharmacol 2003, 478:11–19.

    Article  PubMed  CAS  Google Scholar 

  38. Kenda BM, Matagne AC, Talaga PE, et al.: Discovery of 4-substituted pyrrolidone butanamides as new agents with significant antiepileptic activity. J Med Chem 2004, 47:530–549.

    Article  PubMed  CAS  Google Scholar 

  39. French JA, Brodsky A, von Rosenstiel P, on behalf of the Brivaracetam N01193 Study Group: Efficacy and tolerability of 5, 20 and 50 mg/day brivaracetam (ucb 34714) as adjunctive treatment in adults with refractory partial-onset seizures [abstract]. Epilepsia 2007, 49(Suppl 6):400.

    Google Scholar 

  40. Brown DA, Adams PR: Muscarinic suppression of a novel voltage-sensitive K+ current in a vertebrate neurone. Nature 1980, 283:673–676.

    Article  PubMed  CAS  Google Scholar 

  41. Delmas P, Brown DA: Pathways modulating neural KCNQ/M (Kv7) potassium channels. Nat Rev Neurosci 2005, 6:850–862.

    Article  PubMed  CAS  Google Scholar 

  42. Dalby-Brown W, Hansen HH, Korsgaard MP, et al.: Kv7 channels: function, pharmacology and channel modulators. Curr Top Med Chem 2006, 6:999–1023.

    Article  PubMed  CAS  Google Scholar 

  43. Gu N, Vervaeke K, Hu H, Storm JF: Kv7/KCNQ/M and HCN/h, but not KCa2/SK channels, contribute to the somatic medium after-hyperpolarization and excitability control in CA1 hippocampal pyramidal cells. J Physiol 2005, 566(Pt 3):689–715.

    Article  PubMed  CAS  Google Scholar 

  44. Yue C, Yaari Y: Axo-somatic and apical dendritic Kv7/M channels differentially regulate the intrinsic excitability of adult rat CA1 pyramidal cells. J Neurophysiol 2006, 95:3480–3495.

    Article  PubMed  CAS  Google Scholar 

  45. Yue C, Yaari Y: KCNQ/M channels control spike afterdepolarization and burst generation in hippocampal neurons. J Neurosci 2004, 24:4614–4624.

    Article  PubMed  CAS  Google Scholar 

  46. Rogawski MA: KCNQ2/KCNQ3 K+ channels and the molecular pathogenesis of epilepsy: implications for therapy. Trends Neurosci 2000, 23:393–398.

    Article  PubMed  CAS  Google Scholar 

  47. Maljevic S, Wuttke TV, Lerche H: Nervous system KV7 disorders: breakdown of a subthreshold brake. J Physiol 2008, 586:1791–1801.

    Article  PubMed  CAS  Google Scholar 

  48. Gutman GA, Chandy KG, Grissmer S, et al.: International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol Rev 2005, 57:473–508.

    Article  PubMed  CAS  Google Scholar 

  49. Wang HS, Pan Z, Shi W, et al.: KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 1998, 282:1890–1893.

    Article  PubMed  CAS  Google Scholar 

  50. Lerche C, Scherer CR, Seebohm G, et al.: Molecular cloning and functional expression of KCNQ5, a potassium channel subunit that may contribute to neuronal M-current diversity. J Biol Chem 2000, 275:22395–22400.

    Article  PubMed  CAS  Google Scholar 

  51. Schroeder BC, Hechenberger M, Weinreich F, et al.: KCNQ5, a novel potassium channel broadly expressed in brain, mediates M-type currents. J Biol Chem 2000, 275:24089–24095.

    Article  PubMed  CAS  Google Scholar 

  52. Robbins J: KCNQ potassium channels: physiology, pathophysiology, and pharmacology. Pharmacol Ther 2001, 90:1–19.

    Article  PubMed  CAS  Google Scholar 

  53. Shah MM, Mistry M, Marsh SJ, et al.: Molecular correlates of the M-current in cultured rat hippocampal neurons. J Physiol 2002, 544(Pt 1):29–37.

    Article  PubMed  CAS  Google Scholar 

  54. Roche JP, Westenbroek R, Sorom AJ, et al.: Antibodies and a cysteine-modifying reagent show correspondence of M current in neurons to KCNQ2 and KCNQ3 K+ channels. Br J Pharmacol 2002, 137:1173–1186.

    Article  PubMed  CAS  Google Scholar 

  55. Weber YG, Geiger J, Kämpchen K, et al.: Immunohistochemical analysis of KCNQ2 potassium channels in adult and developing mouse brain. Brain Res 2006, 1077:1–6.

    Article  PubMed  CAS  Google Scholar 

  56. Geiger J, Weber YG, Landwehrmeyer B, et al.: Immunohistochemical analysis of KCNQ3 potassium channels in mouse brain. Neurosci Lett 2006, 400:101–104.

    Article  PubMed  CAS  Google Scholar 

  57. Cooper EC, Aldape KD, Abosch A, et al.: Colocalization and coassembly of two human brain M-type potassium channel subunits that are mutated in epilepsy. Proc Natl Acad Sci U S A 2000, 97:4914–4919.

    Article  PubMed  CAS  Google Scholar 

  58. Lawrence JJ, Saraga F, Churchill JF, et al.: Somatodendritic Kv7/KCNQ/M channels control interspike interval in hippocampal interneurons. J Neurosci 2006, 26:12325–12338.

    Article  PubMed  CAS  Google Scholar 

  59. Hu H, Vervaeke K, Storm JF: M-channels (Kv7/KCNQ channels) that regulate synaptic integration, excitability, and spike pattern of CA1 pyramidal cells are located in the perisomatic region. J Neurosci 2007, 27:1853–1867.

    Article  PubMed  CAS  Google Scholar 

  60. Devaux JJ, Kleopa KA, Cooper EC, Scherer SS: KCNQ2 is a nodal K+ channel. J Neurosci 2004, 24:1236–1244.

    Article  PubMed  CAS  Google Scholar 

  61. Pan Z, Kao T, Horvath Z, et al.: A common ankyrin-G-based mechanism retains KCNQ and NaV channels at electrically active domains of the axon. J Neurosci 2006, 26:2599–2613.

    Article  PubMed  CAS  Google Scholar 

  62. Dzhashiashvili Y, Zhang Y, Galinska J, et al.: Nodes of Ranvier and axon initial segments are ankyrin G-dependent domains that assemble by distinct mechanisms. J Cell Biol 2007, 177:857–870.

    Article  PubMed  CAS  Google Scholar 

  63. Colbert CM, Johnston D: Axonal action-potential initiation and Na+ channel densities in the soma and axon initial segment of subicular pyramidal neurons. J Neurosci 1996, 16:6676–6686.

    PubMed  CAS  Google Scholar 

  64. Schwarz JR, Glassmeier G, Cooper EC, et al.: KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J Physiol 2006, 573:17–34.

    Article  PubMed  CAS  Google Scholar 

  65. Aiken SP, Lampe BJ, Murphy PA, Brown BS: Reduction of spike frequency adaptation and blockade of M-current in rat CA1 pyramidal neurones by linopirdine (DuP 996), a neurotransmitter release enhancer. Br J Pharmacol 1995, 115:1163–1168.

    PubMed  CAS  Google Scholar 

  66. Vickroy TW: Presynaptic cholinergic actions by the putative cognitive enhancing agent DuP 996. J Pharmacol Exp Ther 1993, 264:910–917.

    PubMed  CAS  Google Scholar 

  67. Martire M, Castaldo P, D’Amico M, et al.: M channels containing KCNQ2 subunits modulate norepinephrine, aspartate, and GABA release from hippocampal nerve terminals. J Neurosci 2004, 24:592–597.

    Article  PubMed  CAS  Google Scholar 

  68. Vervaeke K, Gu N, Agdestein C, et al.: Kv7/KCNQ/M-channels in rat glutamatergic hippocampal axons and their role in regulation of excitability and transmitter release. J Physiol 2006, 576:235–256.

    Article  PubMed  CAS  Google Scholar 

  69. Peretz A, Sheinin A, Yue C, 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  PubMed  CAS  Google Scholar 

  70. Parnas H, Parnas I: The chemical synapse goes electric: Ca2+-and voltage-sensitive GPCRs control neurotransmitter release. Trends Neurosci 2007, 30:54–61.

    Article  PubMed  CAS  Google Scholar 

  71. Watanabe H, Nagata E, Kosakai A, et al.: Disruption of the epilepsy KCNQ2 gene results in neural hyperexcitability. J Neurochem 2000, 75:28–33.

    Article  PubMed  CAS  Google Scholar 

  72. Otto JF, Yang Y, Frankel WN, et al.: Mice carrying the szt1 mutation exhibit increased seizure susceptibility and altered sensitivity to compounds acting at the m-channel. Epilepsia 2004, 45:1009–1016.

    Article  PubMed  Google Scholar 

  73. Otto JF, Yang Y, Frankel WN, et al.: A spontaneous mutation involving Kcnq2 (Kv7.2) reduces M-current density and spike frequency adaptation in mouse CA1 neurons. J Neurosci 2006, 26:2053–2059.

    Article  PubMed  CAS  Google Scholar 

  74. Rundfeldt C: The new anticonvulsant retigabine (D-23129) acts as an opener of K+ channels in neuronal cells. Eur J Pharmacol 1997, 336(2–3):243–249.

    Article  PubMed  CAS  Google Scholar 

  75. Rundfeldt C, Netzer R: The novel anticonvulsant retigabine activates M-currents in Chinese hamster ovary-cells tranfected with human KCNQ2/3 subunits. Neurosci Lett 2000, 282:73–76.

    Article  PubMed  CAS  Google Scholar 

  76. Main MJ, Cryan JE, Dupere JR, et al.: Modulation of KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol Pharmacol 2000, 58:253–262.

    PubMed  CAS  Google Scholar 

  77. Wickenden AD, Yu W, Zou A, et al.: Retigabine, a novel anti-convulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol Pharmacol 2000, 58:591–600.

    PubMed  CAS  Google Scholar 

  78. Tatulian L, Delmas P, Abogadie FC, Brown DA: Activation of expressed KCNQ potassium currents and native neuronal M-type potassium currents by the anti-convulsant drug retigabine. J Neurosci 2001, 21:5535–5545.

    PubMed  CAS  Google Scholar 

  79. Tatulian L, Brown DA: Effect of the KCNQ potassium channel opener retigabine on single KCNQ2/3 channels expressed in CHO cells. J Physiol 2003, 549:57–63.

    Article  PubMed  CAS  Google Scholar 

  80. Wuttke TV, Seebohm G, Bail S, et al.: The new anticonvulsant retigabine favors voltage-dependent opening of the Kv7.2 (KCNQ2) channel by binding to its activation gate. Mol Pharmacol 2005, 67:1009–1017.

    Article  PubMed  CAS  Google Scholar 

  81. Schenzer A, Friedrich T, Pusch M, et al.: Molecular determinants of KCNQ (Kv7) K+ channel sensitivity to the anticonvulsant retigabine. J Neurosci 2005, 25:5051–5060.

    Article  PubMed  CAS  Google Scholar 

  82. Piccinin S, Randall AD, Brown JT: KCNQ/Kv7 channel regulation of hippocampal gamma-frequency firing in the absence of synaptic transmission. J Neurophysiol 2006, 95:3105–3112.

    Article  PubMed  CAS  Google Scholar 

  83. Porter RJ, Nohria V, Rundfeldt C: Retigabine. Neurotherapeutics 2007, 4:149–154.

    Article  PubMed  CAS  Google Scholar 

  84. Porter RJ, Partiot A, Sachdeo R, et al.; 205 Study Group: Randomized, multicenter, dose-ranging trial of retigabine for partial-onset seizures. Neurology 2007, 68:1197–1204.

    Article  PubMed  CAS  Google Scholar 

  85. Otto JF, Kimball MM, Wilcox KS: Effects of the anticonvulsant retigabine on cultured cortical neurons: changes in electroresponsive properties and synaptic transmission. Mol Pharmacol 2002, 61:921–927.

    Article  PubMed  CAS  Google Scholar 

  86. Rogawski MA: Diverse mechanisms of antiepileptic drugs in the development pipeline. Epilepsy Res 2006, 69:273–294.

    Article  PubMed  CAS  Google Scholar 

  87. Lawence JJ, Rogawski MA, McBain CJ: The Kv7/KCNQ/M channel opener ICA-027243 arrests interneuronal firing and reduces interneuron network synchrony in the hippocampus: novel insights into the antiepileptic action of Kv7 channel openers [abstract]. Epilepsia 2007, 48(Suppl 6):361.

    Google Scholar 

  88. Wickenden AD, Krajewski JL, London B, et al.: N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): a novel, selective KCNQ2/Q3 potassium channel activator. Mol Pharmacol 2008, 73:977–986.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Michael A. Rogawski.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rogawski, M.A., Bazil, C.W. New molecular targets for antiepileptic drugs: α2δ, SV2A, and Kv7/KCNQ/M potassium channels. Curr Neurol Neurosci Rep 8, 345–352 (2008). https://doi.org/10.1007/s11910-008-0053-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11910-008-0053-7

Keywords

Navigation