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Structural determinants of activity at the GABAB receptor

A comparison of phosphoethanolamine and related GABA analogs

  • Original Articles
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Molecular and Chemical Neuropathology

Abstract

Phosphoethanolamine is a phosphomonoester that is reduced in Alzheimer disease brain. Despite its close structural similarity to GABA and the GABAB partial agonist 3-aminopropylphosphonic acid, phosphoethanolamine binds very poorly to GABAB receptors (IC50=7.5±0.8 mM). In this study, we examined whether the marked decrease in binding affinity associated with the presence of an ester oxygen in place of the α-CH2 group of GABAergic compounds also occurred in sulfonates and used high resolution solution NMR and molecular mechanics calculations to determine the structural basis of this decrease in activity. The sulfonate analog of GABA, 3-aminopropylsulfonic acid, became >2500-fold less potent when the α-CH2 was replaced by an ester oxygen. Structural studies showed that the active α-CH2 compounds (GABA, 3-aminopropylphosphonic acid, and 3-aminopropylsulfonic acid) prefer a fully extended conformation. The inactive compounds, phosphoethanolamine and ethanolamine-O-sulfate, exist in a gauche conformation around the Cβ–Cγ bond. This study, which suggests conformational differences, may explain how PE can be so efficiently excluded from GABAB receptors, despite being present in millimolar concentrations in brain. Exclusion of phosphoethanolamine from GABAB receptors may be an important physiologic control, mechanism in the regulation of inhibitory neurotransmission.

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Abbreviations

3-APP:

3-aminopropylphosphonic acid

3-APS:

3-aminopropylsulfonic acid

EOS:

ethanolamine-O-sulfate

GABA:

γ-aminobutyric acid

PE:

phosphoethanolamine

TMSP:

3-(trimethylsilyl)propionic-2,2,3,3-d4 acid

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Authors and Affiliations

  1. Laboratory of Neurophysics, Department of Psychiatry, Western Psychiatric Institute and Clinic, University of Pittsburgh School of Medicine, A710 Crabtree Hall/GSPH, 130 DeSoto St., 15261, Pittsburgh, PA

    William E. Klunk, Richard J. McClure, Chong-Jun Xu & Jay W. Pettegrew

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  1. William E. Klunk
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  2. Richard J. McClure
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  3. Chong-Jun Xu
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  4. Jay W. Pettegrew
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Klunk, W.E., McClure, R.J., Xu, CJ. et al. Structural determinants of activity at the GABAB receptor. Molecular and Chemical Neuropathology 26, 15–30 (1995). https://doi.org/10.1007/BF02814938

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  • DOI: https://doi.org/10.1007/BF02814938

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