Positive allosteric modulators of AMPA receptors reduce proton-induced receptor desensitization in rat hippocampal neurons.
Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC(50) of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.
Lei
S
S
Departments of Physiology and Pharmacology and Anaesthesia, University of Toronto, Toronto M5S 1A8, Ontario K7L 3N6, Canada. Saobo.lei@utoronto.ca
Orser
B A
BA
Thatcher
G R
GR
Reynolds
J N
JN
MacDonald
J F
JF
D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D001581:Benzothiadiazines / Q000494:pharmacology*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D018698:Glutamic Acid / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects*; D006863:Hydrogen-Ion Concentration; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D009566:Nitrates / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011522:Protons; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects* / Q000502:physiology; D014909:Wheat Germ Agglutinins / Q000494:pharmacology*
D001581:Benzothiadiazines; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D009419:Nerve Tissue Proteins; D009566:Nitrates; D011522:Protons; D011760:Pyrrolidinones; D018091:Receptors, AMPA; D014909:Wheat Germ Agglutinins; D018698:Glutamic Acid; C036466:aniracetam; C004639:cyclothiazide