Dual activation of GABAA and glycine receptors by beta-alanine: inverse modulation by progesterone and 5 alpha-pregnan-3 alpha-ol-20-one.
The differential sensitivity of the glycine and GABAA receptors to modulation by progesterone and 5 alpha-pregnan-3 alpha-ol-20-one (5 alpha 3 alpha) was used to determine whether beta-alanine acts through its own receptor, or through the glycine and/or GABAA receptor(s). The response to beta-alanine resembles the glycine response as it is inhibited by strychnine (a competitive glycine antagonist) or progesterone (a negative modulator of the glycine response). Significantly, the response to beta-alanine also resembles the GABA response in that it is inhibited by 2-(carboxy-3'-propyl)-3-amino-6-paramethoxy-phenylpyridazinium+ ++ bromide (SR-95531; a competitive GABA antagonist) and potentiated by 5 alpha 3 alpha (a positive modulator of the GABA response). The efficacy of beta-alanine at the GABAA receptor is comparable to that of GABA. Similarly, the efficacy of beta-alanine at the glycine receptor is comparable to that of glycine. The greater potency of beta-alanine at the glycine receptor indicates that, if beta-alanine is a neurotransmitter, its effects are more likely to be mediated by glycine receptors than by GABAA receptors. However, activation of the GABAA receptor by beta-alanine may become important in the presence of steroid modulators such as progesterone or 5 alpha 3 alpha.
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Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, MA 02118.
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D000818:Animals; D002478:Cells, Cultured; D002642:Chick Embryo; D018118:Chloride Channels / Q000187:drug effects; D058787:GABA-A Receptor Antagonists; D009474:Neurons / Q000187:drug effects*; D011280:Pregnanolone / Q000494:pharmacology*; D011374:Progesterone / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D018009:Receptors, Glycine / Q000187:drug effects*; D013116:Spinal Cord / Q000166:cytology / Q000187:drug effects; D013331:Strychnine / Q000494:pharmacology; D015091:beta-Alanine / Q000494:pharmacology*
D018118:Chloride Channels; D058787:GABA-A Receptor Antagonists; D011724:Pyridazines; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D015091:beta-Alanine; D011374:Progesterone; C049853:gabazine; D011280:Pregnanolone; D013331:Strychnine