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Methods for Evaluation of Positive Allosteric Modulators of Glutamate AMPA Receptors

  • Edward R. Siuda
  • Jennifer C. Quirk
  • Eric S. Nisenbaum
Part of the Methods in Molecular Biology™ book series (MIMB, volume 403)

Summary

Hypofunctioning of glutamate synaptic transmission in the central nervous system (CNS) has been proposed as a factor that may contribute to cognitive deficits associated with various neurological and psychiatric disorders. Positive allosteric modulation of the α-amino-3-hydroxy-5-methyl-4-isoxazoleproprionic acid (AMPA) subtype of glutamate receptors has been proposed as a novel therapeutic approach, because these receptors mediate the majority of rapid excitatory neurotransmission and are intimately involved in long-term changes in synaptic plasticity thought to underlie mnemonic processing. By definition, positive allosteric modulators do not affect AMPA receptor activity alone but can markedly enhance ion flux through the ion channel pore in the presence of bound agonist. Despite this commonality, positive allosteric modulators can be segregated on the basis of the preferential effects on AMPA receptor subunits, their alternatively spliced variants and/or their biophysical mechanism of action. This chapter provides a detailed description of the methodologies used to evaluate the potency/efficacy and biophysical mechanism of action of positive allosteric modulators of AMPA receptors.

Key Words

AMPA glutamate desensitization deactivation LY503430 cyclothiazide GluR2 positive allosteric modulator 

Notes

Acknowledgements

The authors thank Mark Fleck PhD and Elizabeth Cornell for assistance with the outside-out patch recording technique.

References

  1. 1.
    Yamada KA (2000) Therapeutic potential of positive AMPA receptor modulators in the treatment of neurological disease. Expert Opin Investig Drugs 9:765–778.CrossRefPubMedGoogle Scholar
  2. 2.
    Staubli U, Rogers G, Lynch G (1994) Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci USA 91:777–781.Google Scholar
  3. 3.
    Sekiguchi M, Yamada K, Jin J, Hachitanda M, Murata Y, Namura S, Kamichi S, Kimura I, Wada K (2001) The AMPA receptor allosteric potentiator PEPA ameliorates post-ischemic memory impairment. NeuroReport 12:2947–2950.CrossRefPubMedGoogle Scholar
  4. 4.
    Oepen G, Eisele K, Thoden U, Birg W (1985) Piracetam improves visuomotor and cognitive deficits in early Parkinsonism–a pilot study. Pharmacopsychiatry 18:343–346.CrossRefPubMedGoogle Scholar
  5. 5.
    Ingvar M, Ambros-Ingerson J, Davis M, Granger R, Kessler M, Rogers GA, Schehr RS, Lynch G (1997) Enhancement by an ampakine of memory encoding in humans. Exp Neurol 146:553–559.CrossRefPubMedGoogle Scholar
  6. 6.
    Dimond SJ, Scammell RE, Pryce IG, Huws D, Gray C (1979) Some effects of piracetam (UCB 6215 Nootropyl) on chronic schizophrenia. Psychopharmacology 64:341–348.CrossRefPubMedGoogle Scholar
  7. 7.
    Hampson RE, Rogers G, Lynch G, Deadwyler SA (1998) Facilitative effects of the ampakine CX516 on short-term memory in rats: correlations with hippocampal neuronal activity. J Neurosci 18:2748–2763.PubMedGoogle Scholar
  8. 8.
    Burnashev N, Monyer H, Seeburg PH, Sakmann B (1992) Divalent ion permeability of AMPA receptor channels is dominated by the edited form of a single subunit. Neuron 8(1): 189–198.CrossRefPubMedGoogle Scholar
  9. 9.
    Jonas P, Sakmann B (1992) Glutamate receptor channels in isolated patches from CA1 and CA3 pyramidal cells of rat hippocampal slices. J Physiol 455: 143–171.PubMedGoogle Scholar
  10. 10.
    Raman IM, Trussell LO (1995) The mechanism of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate receptor desensitization after removal of glutamate. Biophys J 68:137–146.CrossRefPubMedGoogle Scholar
  11. 11.
    Lambolez B, Audinat E, Bochet P, Crepel F, Rossier J (1992) AMPA receptor subunits expressed by single Purkinje cells. Neuron 9(2): 247–258.CrossRefPubMedGoogle Scholar
  12. 12.
    Geiger JR, Melcher T, Koh DS, Sakmann B, Seeburg PH, Jonas P, Monyer H (1995) Relative abundance of subunit mRNAs determines gating and Ca2+ permeability of AMPA receptors in principal neurons and interneurons in rat CNS. Neuron 15(1):193–204.CrossRefPubMedGoogle Scholar
  13. 13.
    Keinanen K, Wisden W, Sommer B, Werner P, Herb A, Verdoorn TA, Sakmann B, Seeburg PH (1990) A family of AMPA-selective glutamate receptors. Science 249:556–560.CrossRefPubMedGoogle Scholar
  14. 14.
    Sommer B, Keinanen K, Verdoorn TA, Wisden W, Burnashev N, Herb A, Kohler M, Takagi T, Sakmann B, Seeburg PH (1990) Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249: 1580–1585.CrossRefPubMedGoogle Scholar
  15. 15.
    Hollmann M, O’Shea-Greenfield A, Rogers SW, Heinemann S (1989) Cloning and functional expression of a member of the glutamate receptor family. Nature 342:643–648.CrossRefPubMedGoogle Scholar
  16. 16.
    Staubli U, Perez Y, Xu F, Rogers G, Ingvar M, Stone-Elander S, Lynch G (1994) Centrally active modulators of glutamate receptors facilitate the induction of long-term potentiation in vivo. Proc Natl Acad Sci USA 91:11158–11162.CrossRefGoogle Scholar
  17. 17.
    Armstrong N, Sun Y, Chen GQ, Gouaux E (1998) Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature 395(6705):913–917.CrossRefPubMedGoogle Scholar
  18. 18.
    Baddeley A. (1992) Working memory. Science 255:556–559.CrossRefPubMedGoogle Scholar
  19. 19.
    Dudkin KN, Kruchinin VK, Chueva IV (1997) Synchronization processes in the mechanisms of short-term memory in monkeys: the involvement of cholinergic and glutaminergic cortical structures. Neurosci Behav Physiol 27: 303–308.CrossRefPubMedGoogle Scholar
  20. 20.
    Mayer M, Vyklicky L Jr. (1989) Concanavalin A selectively reduces desensitization of mammalian neuronal quisqualate receptors. Proc Natl Acad Sci USA 86:1411–1415.CrossRefPubMedGoogle Scholar
  21. 21.
    Brown TH, Chapman PF, Kairiss EW, Keenan CL (1988) Long-term synaptic potentiation. Science 242(4879):724–728.CrossRefPubMedGoogle Scholar
  22. 22.
    Carlsson A, Waters N, Holm-Waters S, Tedroff J, Nilsson M, Carlsson ML (2001) Interactions between monoamines, glutamate, and GABA in schizophrenia: new evidence. Annu Rev Pharmacol Toxicol 41:237–260.CrossRefPubMedGoogle Scholar
  23. 23.
    Carlsson ML (2001) On the role of cortical glutamate in obsessive-compulsive disorder and attention-deficit hyperactivity disorder, two phenomenologically antithetical conditions. Acta Psychiatr Scand 102(6):401–413.CrossRefGoogle Scholar
  24. 24.
    Chen Q, Flores-Hernandez JF, Jiao Y, Reiner A, Surmeier DJ (1998) Physiological and molecular properties of AMPA/kainate receptors expressed by striatal medium spiny neurons. Develop Neurosci 20:242–252.CrossRefGoogle Scholar
  25. 25.
    Coyle JT (1996) The glutamatergic dysfunction hypothesis for schizophrenia. Harv Rev Psychiatry 3(5):241–253.CrossRefPubMedGoogle Scholar
  26. 26.
    Dingledine R, Borges K, Bowie D, Traynelis SF (1999) The glutamate receptor ion channels. Pharmacol Rev 51(1):7–61.PubMedGoogle Scholar
  27. 27.
    Eastwood SL, Burnet PW, Harrison PJ (1997) GluR2 glutamate receptor subunit flip and flop isoforms are decreased in the hippocampal formation in schizophrenia: a reverse transcriptase-polymerase chain reaction (RT-PCR) study. Brain Res Mol Brain Res 44(1):92–98.CrossRefPubMedGoogle Scholar
  28. 28.
    Barkley R, Grodzinsky G, DuPaul G (1992) Frontal lobe functions in attention deficity disorder with and without hyperactivity: a review and research report. J Abnorm Child Psychol 2;20:163–188.CrossRefGoogle Scholar
  29. 29.
    Baumbarger PJ, Muhlhauser M, Zhai J, Yang CR, Nisenbaum ES (2001) Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors in prefrontal cortical pyramidal neurons by a novel allosteric potentiator. J Pharmacol Exp Ther 298(1):86–102.PubMedGoogle Scholar
  30. 30.
    Benson D (1991) The role of frontal dysfunction in attention deficit hyperactivity disorder. J Child Neurol 6(suppl):S9–S12.Google Scholar
  31. 31.
    Bleakman D, Gates MR, Ogden A, Ornstein PL, Zarrinmayeh H, Nisenbaum ES, Baumbarger P, Jarvie KR, Miu P, Ho K et al. (2000). Novel AMPA receptor potentiators LY392098 and LY404187: effects on recombinant human and rat neuronal AMPA receptors. Soc Neurosci Abstr 30:173.Google Scholar
  32. 32.
    Arai A, Lynch G (1992) Factors regulating the magnitude of long-term potentiation induced by theta pattern stimulation. Brain Res 598:173–184.CrossRefPubMedGoogle Scholar
  33. 33.
    Armstrong N, Gouaux E (2000) Mechanisms for Activation and Antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core. Neuron 28:165–181.CrossRefPubMedGoogle Scholar
  34. 34.
    Quirk JC, Siuda ER, Nisenbaum ES (2004) Molecular determinants responsible for differences in desensitization kinetics of AMPA receptor splice variants. J Neurosci 24(50): 11416–11420.CrossRefPubMedGoogle Scholar
  35. 35.
    Yelshansky MV, Sobolevsky AI, Jatzke C, Wollmuth LP (2004) Block of AMPA receptor desensitization by a point mutation outside the ligand-binding domain. J Neurosci 24(20):4728–4736.CrossRefPubMedGoogle Scholar
  36. 36.
    Koike M, Tsukada S, Tsuzuki K, Kijima H, Ozawa S. (2000) Regulation of kinetic properties of GluR2 AMPA receptor channels by alternative splicing. J Neurosci 20(6):2166–2174.PubMedGoogle Scholar
  37. 37.
    Grosskreutz J, Zoerner A, Schlesinger F, Krampfl K, Dengler R, Bufler J. (2003) Kinetic properties of human AMPA-type glutamate receptors expressed in HEK293 cells. Eur J Neurosci 17(6):1173–1178.CrossRefPubMedGoogle Scholar
  38. 38.
    Partin KM, Fleck MW, Mayer ML (1996) AMPA Receptor flip/flop mutants affecting deactivation, desensitization, and modulation of cyclothiazide, aniracetam and thiocyanate. J Neurosci 16(21):6634–6647.PubMedGoogle Scholar
  39. 39.
    Hille B (2001) Ion Channels of Excitable Membranes. Sinaur Associates, Sunderland, MA.Google Scholar
  40. 40.
    Swanson GT, Kamboj SK, Cull-Candy SG (1997) Single-channel properties of recombinant AMPA receptors depend on RNA editing, splice variation, and subunit composition. J Neurosci 17:58–69.PubMedGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  • Edward R. Siuda
  • Jennifer C. Quirk
  • Eric S. Nisenbaum

There are no affiliations available

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