Methods for Evaluation of Positive Allosteric Modulators of Glutamate AMPA Receptors
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 WordsAMPA glutamate desensitization deactivation LY503430 cyclothiazide GluR2 positive allosteric modulator
The authors thank Mark Fleck PhD and Elizabeth Cornell for assistance with the outside-out patch recording technique.
- 2.Staubli U, Rogers G, Lynch G (1994) Facilitation of glutamate receptors enhances memory. Proc Natl Acad Sci USA 91:777–781.Google Scholar
- 30.Benson D (1991) The role of frontal dysfunction in attention deficit hyperactivity disorder. J Child Neurol 6(suppl):S9–S12.Google Scholar
- 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
- 39.Hille B (2001) Ion Channels of Excitable Membranes. Sinaur Associates, Sunderland, MA.Google Scholar