Skip to main content
SpringerLink
Log in

Die α2δ-Untereinheit der spannungsabhängigen Kalziumkanäle

Ein neues pharmakologisches Ziel in der Psychiatrie und Neurologie

The α2δ subunit of the tension-dependent calcium channel

  • Aktuelles
  • Published:
Der Nervenarzt Aims and scope Submit manuscript

Zusammenfassung

Bei dem Wort „Kalziumkanalblocker“ denken Kliniker vor allem an Mittel zur Behandlung des Bluthochdrucks und der koronaren Herzkrankheit. Jetzt gibt es Medikamente, die ebenfalls Kalziumkanäle modulieren und die wegen ihres neuen Wirkmechanismus interessante Neuentwicklungen im Bereich psychiatrischer und neurologischer Indikationen darstellen können. Gabapentin und Pregabalin binden an eine Untereinheit von Kalziumkanälen, α2δ-Rezeptoren. Dadurch wird der Kalziumeinstrom in die Nervenzelle reduziert. Als Folge wird weniger Glutamat aus denjenigen Nervenendigungen freigesetzt, die exzitatorische Aminosäuren als Transmitter verwenden. So kommt es zu einer verringerten Substanz-P-unterstützten Aktivierung von AMPA-Heterorezeptoren an noradrenergen Synapsen. Als Folge werden die Transmitterausschüttung und die Aktivität der Neuronen gehemmt. Dieser Mechanismus ist möglicherweise dafür verantwortlich, dass die Medikamente Gabapentin und Pregabalin nicht nur bei neuropathischen Schmerzen, sondern auch antikonvulsiv und anxiolytisch wirken können.

Summary

Calcium channel blockers are substances used for treating high blood pressure and coronary heart disease. New medications have been developed that modulate calcium channels but also show promise in psychiatric and neurologic applications. Gabapentin and pregabalin bind to a subunit of calcium channels — the α2δ receptors — thereby reducing calcium influx to neurons. As a result, less glutamate is released from nerve endings that use excitatory amino acids as transmitters. This in turn reduces substance P-related activation of AMPA heteroreceptors on noradrenergic synapses, total transmitter release, and finally neuronal activity. That mechanism is the probable explanation for gabapentin’s and pregabalin’s usefullness in the treatment of neuropathic pain but also their possible anticonvulsive and anxiolytic effects.

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

Abb. 1

Literatur

  1. Arikkoth J, Campbell KP (2003) Auxiliary subunits: essential components of the voltage-gated calcium channel complex. Curr Opin Neurobiol 13:298–307

    Google Scholar 

  2. Arroyo S, Anhut H, Kugler AR et al. (2004) Pregabalin add-on treatment: a randomized, double-blind, placebo-controlled, dose-response study in adults with partial seizures. Epilepsia 45:20–27

    Article  CAS  Google Scholar 

  3. Brust PF, Simerson S, McCue AF et al. (1993) Human neuronal voltage-dependent calcium channels: studies on subunit structure and role in channel assembly. Neuropharmacology 32:1089–1102

    Article  CAS  PubMed  Google Scholar 

  4. Dooley DJ, Donovan CM, Pugsley TA (2000) Stimulus-dependent modulation of [(3)H] norepinephrine release from rat neocortical slices by gabapentin and pregabalin. J Pharmacol Exp Ther 295:1086–1093

    CAS  PubMed  Google Scholar 

  5. Dworkin RH, Corbin AE, Young JPJr et al. (2003) Pregabalin for the treatment of postherpetic neuralgia: a randomized, placebo-controlled trial. Neurology 60:1274–1283

    CAS  PubMed  Google Scholar 

  6. Feltner DE, Pollack MH, Davidson JRT (2000) A placebo-controlled study of pregabalin in the treatment of social phobia. Abstract, Anxiety Disorders Of America’s 20th Annual Conference, Washington

  7. Feltner DE, Crockatt JG, Dubovsky SJ et al. (2003) A randomized, double-blind, placebo-controlled, fixed-dose, multicenter study of pregabalin in patients with generalized anxiety disorder. J Clin Psychopharmacol 23:240–249

    Google Scholar 

  8. Fink K, Dooley DJ, Meder WP et al. (2002) Inhibition of neuronal Ca (2+) influx by gabapentin and pregabalin in the human neocortex. Neuropsychopharmacology 42:229–236

    Article  CAS  Google Scholar 

  9. Frampton JE, Foster RH (2005) Pregabalin: in the treatment of postherpetic neuralgia. Drugs 65:111–118

    PubMed  Google Scholar 

  10. Frampton JE, Scott LJ (2004) Pregabalin: in the treatment of painful diabetic peripheral neuropathy. Drugs 64:2813–2820

    CAS  PubMed  Google Scholar 

  11. French JA, Kugler AR, Robbins JL et al. (2003) Dose-response trial of pregabalin adjunctive therapy in patients with partial seizures. Neurology 60:1631–1637

    CAS  PubMed  Google Scholar 

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

    Google Scholar 

  13. Hofman F, Biel M, Flockerzi V (1994) Molecular basis for Ca (2+) channel diversity. Annu Rev Neurosci 17:399–418

    Article  PubMed  Google Scholar 

  14. Isom LL, De Jongh KS, Caterall WA (1994) Auxiliary subunits of voltage-gated ion channels. Neuron 12:1183–1194

    Article  CAS  PubMed  Google Scholar 

  15. Klugbauer N, Lacinova L, Marais E et al. (1999) Molecular diversity of the calcium channel alpha2delta subunit. J Neurosci 19:684–691

    Google Scholar 

  16. Lauria-Horner BA, Pohl RB (2003) Pregabalin: a new anxiolytic. Expert Opin Investig Drugs 12:663–672

    Article  CAS  PubMed  Google Scholar 

  17. Lesser H, Sharma U, LaMoreaux L et al. (2004) Pregabalin relieves symptoms of painful diabetic neuropathy: a randomized controlled trial. Neurology 63:2104–2110

    CAS  PubMed  Google Scholar 

  18. Maneuf YP, McKnight AT (2000) Gabapentin inhibits substance P- and calcitonin gene-related peptide-facilitated K+-evoked release of [3H]-glutamate from rat caudal trigeminal nucleus slices. Soc Neurosci 26:722–729

    Google Scholar 

  19. Maneuf YP, Hughes J, McKnight AT (2001) Gabapentin inhibits substance P-facilitated K(+)-evoked release of [(3)H] glutamate from rat caudal trigeminal nucleus slices. Pain 93:191–196

    Article  CAS  PubMed  Google Scholar 

  20. Martin DJ, McClelland D, Herd MB et al. (2002) Gabapentin-mediated inhibition of voltage-activated Ca2+ channel currents in cultured sensory neurones is dependent on culture conditions and channel subunit expression. Neuropharmacology 42:353–366

    Google Scholar 

  21. McGivern JG, McDonough SI (2004) Voltage-gated calcium channels as targets for the treatment of chronic pain. Curr Drug Target CNS Neurol Disord 3:457–478

    Article  CAS  Google Scholar 

  22. Pande AC, Davidson JR, Jefferson JW et al. (1999) Treatment of social phobia with gabapentin: a placebo-controlled study. J Clin Psychopharmacol 19:341–348

    Google Scholar 

  23. Pande AC, Pollack MH, Crockatt J et al. (2000) Placebo-controlled study of gabapentin treatment of panic disorder. J Clin Psychopharmacol 20:467–471

    Article  CAS  PubMed  Google Scholar 

  24. Pande AC, Crockatt JG, Feltner DE et al. (2003) Pregabalin in generalized anxiety disorder: a placebo-controlled trial. Am J Psychiatry 160:533–540

    Article  PubMed  Google Scholar 

  25. Pande AC, Feltner DE, Jefferson JW et al. (2004) Efficacy of the novel anxiolytic pregabalin in social anxiety disorder: a placebo-controlled, multicenter study. J Clin Psychopharmacol 24:141–149

    Google Scholar 

  26. Reichling DB, Levine JD (1999) The primary afferent nociceptor as a pattern generator. Pain 6(Suppl):103–109

    Article  Google Scholar 

  27. Rosenstock J, Tuchman M, LaMoreaux L et al. (2004) Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial. Pain 110:628-638

    Article  CAS  PubMed  Google Scholar 

  28. Sieghart W (2003) Benzodiazepines, benzodiazepine receptors, and endogeneous ligands. In: Kasper S, den Boer JA, Ad Sitsen JM (eds) Handbook of depression and anxiety. Dekker, New York, pp 415–442

  29. Su T, Gong CH, Hang J et al. (2000) Human α2δ2 subunit of calcium channel: a novel gabapentin binding protein in brain. Soc Neurosci 26:40.20

    Google Scholar 

  30. Sutton KG, Martin DJ, Pinnock RD et al. (2002) Gabapentin inhibits high-threshold calcium channel currents in cultured rat dorsal root ganglion neurons. Br J Pharmacol 135:257–265

    Google Scholar 

  31. Taylor CP, Vartanian MG, Yuen PW et al. (1993) Potent and stereospecific anticonvulsant activity of 3-isobutyl GABA relates to in vitro binding at a novel site labelled by tritiated gabapentin. Epilepsy Res 14:11–15

    Article  CAS  PubMed  Google Scholar 

  32. Thurlow RJ, Brown JP, Gee NS et al. (1993) [3H] gabapentin may label a system-L-like neutral amino acid carrier in brain. Eur J Pharmacol 247:341–345

    Article  CAS  PubMed  Google Scholar 

  33. Walker D, De Waard M (1998) Subunit interaction sites in voltage-dependent Ca(2+) channels: role in channel function. Trends Neurosci 21:148–154

    Article  CAS  PubMed  Google Scholar 

  34. Williams ME, Feldman DH, McCue AF et al. (1992) Structure and functional expression of alpha 1, alpha 2, and beta subunits of a novel human neuronal calcium channel subtype. Neuron 8:71–84

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Psychiatrie und Psychotherapie der Georg-August-Universität Göttingen

    D. Wedekind &  B. Bandelow

  2. Klinik für Psychiatrie und Psychotherapie der Georg-August-Universität Göttingen, von-Siebold-Straße 5, 37075, Göttingen, Deutschland

    B. Bandelow

Authors
  1. D. Wedekind
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. B. Bandelow
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to B. Bandelow.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wedekind, D., Bandelow, B. Die α2δ-Untereinheit der spannungsabhängigen Kalziumkanäle. Nervenarzt 76, 888–892 (2005). https://doi.org/10.1007/s00115-005-1940-7

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00115-005-1940-7

Schlüsselwörter

Keywords

Search

Navigation