Pharmacological effects of AMPA receptor potentiators LY392098 and LY404187 on rat neuronal AMPA receptors in vitro
Introduction
In the mammalian central nervous system, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors are a subset of excitatory amino acid glutamate receptors (Collingridge and Lester, 1989, Bleakman and Lodge, 1998). AMPA receptors are comprised of up to four receptor subunits GluR1, GluR2, GluR3 and GluR4 in hetero-oligomeric complexes (Seeberg, 1993, Hollmann and Heinemann, 1994). Additional receptor diversity is afforded on AMPA receptor subunits by alternatively spliced isoforms of the subunits (flip (i) and flop (o)) and RNA editing of the GluR2 subunit (Seeberg et al., 1998, Dev and Henley, 1998). Although the exact stoichiometry of the AMPA receptor complex is unknown, recombinant expression studies have demonstrated that the presence or absence of subunits and/or subunit variants can markedly affect the pharmacological and biophysical properties of the resultant ion channels.
There have been several molecules shown to positively and negatively modulate ion influx through recombinant and neuronal AMPA receptors via an allosteric mechanism of action. Negative allosteric modulators include the non-competitive antagonist 2,3-benzodiazepine series of compounds (Vizi et al., 1996). Positive allosteric modulators include the nootropic pyrrolidones (aniracetam, oxiracetam, piracetam) and related compounds such as CX516 (Ito et al., 1990, Staubli et al., 1990, Copani et al., 1992, Arai et al., 1994) and the benzothiadiazides (cyclothiazide, diazoxide, IDRA-21) (Vyklicky et al., 1991, Yamada and Rothman, 1992, Thompson et al., 1995). An additional compound that has been shown to positively modulate AMPA receptors is PEPA (Sekiguchi et al., 1997). We have demonstrated that the two novel compounds, LY392098 and LY404187 (Ornstein et al., 2000) reversibly potentiate recombinant human AMPA receptor responses (Miu et al., 2001). In the present study, we have used two neuronal preparations to examine the pharmacological effects of these compounds at neuronal AMPA receptors and to compare their activity to the known AMPA receptor potentiators. We have also examined their activity at other ion channels. A preliminary report of this work has been presented (Bleakman et al., 2000).
Section snippets
Electrophysiological recording conditions
Whole-cell voltage clamp recordings (Vh= −70 mV) were made from single neuronal cell bodies with the use of the tight seal whole-cell configuration of the patch-clamp technique (Hamill et al., 1981). Glass fragments of cover slips with adherent cells were placed in a perfusion chamber and rinsed with buffer of composition: 138 mM NaCl, 5 mM CaCl2, 5 mM KCl, 1 mM MgCl2, 10 mM HEPES and 10 mM glucose, pH of 7.5 with NaOH (osmolality 315 mosm/kg). Pipette solutions contained 140 mM CsC1, 1 mM MgC12, 14 mM
Cerebellar Purkinje neurons
Steady-state inward currents under whole-cell recording conditions were activated in cerebellar Purkinje cells by application of glutamate (100 μM) to isolated cells. Glutamate responses were completely inhibited by the non-competitive 2,3-benzodiazepine AMPA receptor antagonist, LY300168 (50 μM) (not shown). Since glutamate was used as the agonist, we also investigated whether functional NMDA receptors were present in acutely isolated cerebellar Purkinje neurons. Currents were not elicited when
Discussion
Allosteric modulators have been identified for NMDA, AMPA and kainate subtypes of glutamate receptors (Collingridge and Lester, 1989, Bleakman and Lodge, 1998). For AMPA receptors, positive modulator compounds have been used in recent years to probe the allosteric binding sites for AMPA receptors and also to investigate the therapeutic potential for compounds that mechanistically alter glutamatergic neurotransmission. The known AMPA receptor potentiators are of three general types, the
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