Premium
Mechanisms of anabolic androgenic steroid inhibition of mammalian ɛ‐subunit‐containing GABA A receptors
Author(s) -
Jones Brian L.,
Whiting Paul J.,
Henderson Leslie P.
Publication year - 2006
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2006.106534
Subject(s) - gabaa receptor , endocrinology , medicine , picrotoxin , receptor , chemistry , gabaergic , population , bicuculline , biology , gamma aminobutyric acid , environmental health
GABAergic transmission regulates the activity of gonadotrophin‐releasing hormone (GnRH) neurons in the preoptic area/hypothalamus that control the onset of puberty and the expression of reproductive behaviours. One of the hallmarks of illicit use of anabolic androgenic steroids (AAS) is disruption of behaviours under neuroendocrine control. GnRH neurons are among a limited population of cells that express high levels of the ɛ‐subunit of the GABA A receptor. To better understand the actions of AAS on neuroendocrine mechanisms, we have characterized modulation of GABA A receptor‐mediated currents in mouse native GnRH neurons and in heterologous cells expressing recombinant α 2 β 3 ɛ‐receptors. GnRH neurons exhibited robust currents in response to millimolar concentrations of GABA and a picrotoxin (PTX)‐sensitive, bicuculline‐insensitive current that probably arises from spontaneous openings of GABA A receptors. The AAS 17α‐methyltestosterone (17α‐MeT) inhibited spontaneous and GABA‐evoked currents in GnRH neurons. For recombinant α 2 β 3 ɛ‐receptors, 17α‐MeT inhibited phasic and tonic GABA‐elicited responses, accelerated desensitization and slowed paired pulse response recovery. Single channel analysis indicated that GABA‐evoked events could be described by three open dwell components and that 17α‐MeT enhanced residence in the intermediate dwell state. This AAS also inhibited a PTX‐sensitive, spontaneous current (open probability, ∼0.15–0.2) in a concentration‐dependent fashion (IC 50 ≈ 9 μ m ). Kinetic modelling indicated that the inhibition induced by 17α‐MeT occurs by an allosteric block in which the AAS interacts preferentially with a closed state and promotes accumulation in that state. Finally, studies with a G302S mutant ɛ‐subunit suggest that this residue within the transmembrane domain TM2 plays a role in mediating AAS binding and modulation. In sum, our results indicate that inclusion of the ɛ‐subunit significantly alters the profile of AAS modulation and that this allosteric inhibition of native GnRH neurons should be considered with regard to AAS disruption of neuroendocrine control.