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γ-hydroxybutyrate (GHB) is a small molecule with complex pharmacology. Present in low concentrations in the mammalian brain, it acts as a neuromodulator. When taken exogenously, it is used to treat narcolepsy and to ameliorate the withdrawal effects of alcohol, and is used as a recreational drug at higher concentrations, sometimes used as a “date-rape” drug. However, the pharmacology of GHB is unclear, and the full extent of its interactions with membrane proteins in the brain is yet to be fully elucidated. It has been demonstrated that GHB activates the GABAB receptor at high concentrations, but the receptor that mediates other actions of GHB has yet to be identified. We have demonstrated through ligand-binding studies and two-electrode voltage clamp electrophysiology that GHB binds to specific cys-loop ligand-gated ion channels, α4β1-3δ γ-aminobutyric acid (GABAA) receptors, in the brain. We hypothesize that these receptors mediate part of the physiological effects of GHB. To fully understand the range of GABAA receptors, which comprise the so-called “GHB receptors,” we have employed a range of methods including ligand-binding studies of mice lacking GABAAR subunits of interest, electrophysiology of receptors containing mutations at the interface of two subunits and manipulation of relative amounts of RNA of subunits injected into the oocyte. We have demonstrated that the α4-subunit is essential for binding of approximately half of the “GHB receptors” in the brain, and that the relative level of β-subunits within the GHB complex affects the function of GHB at these receptors. We hypothesize that GHB may exert physiological effects via interactions at the same receptor.

参考文献
Absalom N et al. α4βδ GABAA receptors are high-affinity targets for γｰhydroxybutyric acid (GHB). Proc Natl Acad Sci USA (2012) 109: 13404-13409.