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Modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor desensitization by extracellular
1Committee on Neurobiology and Department of Neurobiology, Pharmacology and Physiology, University of Chicago, Chicago, Illinois, USA.
Molecular Pharmacology
|November 28, 2000
Summary
Brain interstitial acidification, common in ischemia, inhibits AMPA receptor function. This pH effect on glutamate receptors may explain why some neurons are more vulnerable during ischemic events.
Area of Science:
- Neuroscience
- Molecular Biology
- Physiology
Background:
- Brain interstitial pH is typically 7.3 but can decrease during events like ischemia and seizures.
- Changes in pH can alter neuronal excitability by affecting receptors and channels.
- AMPA receptors are crucial for synaptic transmission in the brain.
Purpose of the Study:
- To investigate the impact of physiologically relevant pH changes on AMPA receptor function in cultured rat hippocampal neurons.
- To determine if acidic pH, mimicking ischemic conditions, affects AMPA receptor-mediated responses.
- To explore the mechanisms by which protons modulate AMPA receptor desensitization and identify molecular determinants.
Main Methods:
- Patch-clamp recordings from cultured rat hippocampal neurons.
- Application of varying pH levels (6.5-7.8) and AMPA receptor agonists (glutamate, quisqualate, kainate).
- Experiments using desensitization-blocking drugs and recombinant AMPA receptors in HEK 293 cells.
Main Results:
- Acidic pH (6.5) significantly inhibited AMPA receptor-mediated responses, with greater inhibition for strongly desensitizing agonists.
- Protons increased equilibrium desensitization of AMPA receptors but did not affect macroscopic desensitization or deactivation kinetics.
- Inhibition of kainate-evoked responses varied by AMPA receptor subunit and isoform composition, with 'flop' isoforms being most sensitive.
Conclusions:
- Interstitial acidification modulates AMPA receptor-mediated synaptic transmission.
- Differences in AMPA receptor sensitivity to protons may contribute to the selective vulnerability of neuronal populations during ischemia.
- Proton-induced modulation of AMPA receptor desensitization is a key mechanism underlying these effects.
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