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Journal of Neuroscience, Vol 14, 3881-3897, Copyright © 1994 by Society for Neuroscience
Willardiines differentiate agonist binding sites for kainate- versus AMPA-preferring glutamate receptors in DRG and hippocampal neurons
LA Wong, ML Mayer, DE Jane and JC Watkins
Laboratory of Cellular and Molecular Neurophysiology, NICHD, National Institutes of Health, Bethesda, Maryland 20892.
Concentration jump responses to 5-substituted (S)-willardiines were
recorded from dorsal root ganglion (DRG) and hippocampal neurons under
voltage clamp. After block of desensitization by concanavalin-A, dose-
response analysis for activation of kainate-preferring receptors in DRG
neurons gave the potency sequence trifluoromethyl > iodo > bromo
approximately chloro > nitro approximately cyano > kainate >
methyl > fluoro > (R,S)-AMPA >> willardiine; EC50 values for
the most and least potent willardiine derivatives, 5-trifluoromethyl (70
nM) and 5-fluoro (69 microM), differed 1000-fold. The potency sequence for
equilibrium responses at AMPA-preferring receptors in hippocampal neurons
was strikingly different from that obtained in DRG neurons: fluoro >
cyano approximately trifluoromethyl approximately nitro > chloro
approximately bromo > (R,S)-AMPA > iodo > willardiine > kainate
> methyl. In hippocampal neurons EC50 values for the most and least
potent willardiine derivatives, 5-fluoro (1.5 microM) and 5-methyl (251
microM), differed only 170-fold. Consistent with equilibrium potency
measurements, in DRG neurons the kinetics of deactivation for willardiines,
recorded following a return to agonist-free solution, were rapid for
5-fluoro (tau off = 43 msec) but slow for 5-iodo (tau off = 4.2 sec), while
the opposite sequence was observed for hippocampal neurons, slow for
5-fluoro (tau off = 2.1 sec) and rapid for 5-iodo (tau off = 188 msec). The
kinetics of recovery from desensitization showed comparable agonist- and
cell-dependent differences. Structure-activity analysis for agonist
responses recorded from DRG and hippocampal neurons suggests that for both
kainate- preferring and AMPA-preferring receptors the binding of
willardiines involves interactions with polar groups such that potency is
related to ionization of the uracil ring, and hence the
electron-withdrawing ability of the 5-position substituent. However,
kainate-preferring receptors differ from AMPA-preferring receptors in
possessing a lipophilic pocket that further enhances agonist potency by
hydrophobic bonding of the 5-substituent. In contrast, AMPA-preferring
receptors lack such a lipophilic site, and for 5-position substituents of
the same electron-withdrawing ability, potency decreases with increase in
size.
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