Role of the alpha subunit in the modulation of GABA(A) receptors by anabolic androgenic steroids.
Neural transmission mediated by circuits expressing alpha2 subunit-containing gamma-aminobutyric acid type A (GABA(A)) receptors is critical for the expression of behaviors known to be altered by anabolic androgenic steroids (AAS). Here we show that micromolar concentrations of AAS, which reflect levels found in steroid abusers, induce positive modulation of currents from alpha2beta3 gamma2L recombinant receptors elicited by pulses of GABA that mimic synaptic conditions in a manner that is mechanistically distinct from modulation induced at alpha1beta3 gamma2L receptors. Specifically, at alpha2-containing receptors, the AAS, 17alpha-methyltestosterone (17alpha-MeT) enhanced peak current, slowed deactivation, diminished desensitization, and promoted entry of receptors into more distal states along the activation pathway. Analysis of GABA(A) receptor-mediated synaptic currents in primary cortical neurons followed by single cell real-time RT-PCR demonstrated that 17alpha-MeT enhancement of synaptic currents is proportional to the ratio of alpha2 to alpha1 subunit mRNA. Finally, we show that the modulation elicited by AAS is not comparable to that produced by micromolar concentrations of other positive allosteric modulators at alpha2-containing receptors. In sum, these data indicate that AAS elicit effects on GABA(A) receptor function that depend significantly on alpha subunit composition and that the mechanism of AAS modulation of GABA(A) receptors is distinct from that of other positive allosteric modulators.
Department of Physiology, Dartmouth Medical School, Hanover, NH 03755, USA.
Paul
P
Yang
Brian L
BL
Jones
Leslie P
LP
Henderson
D045930:Anabolic Agents / Q000494:pharmacology*; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005260:Female; D018755:GABA Agonists / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D015233:Models, Statistical; D009474:Neurons / Q000187:drug effects; D018408:Patch-Clamp Techniques; D011247:Pregnancy; D021122:Protein Subunits / Q000187:drug effects* / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013569:Synapses / Q000502:physiology; D045165:Testosterone Congeners / Q000494:pharmacology*; D014162:Transfection; D000077334:Zolpidem; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D045930:Anabolic Agents; D014151:Anti-Anxiety Agents; D018755:GABA Agonists; C493920:Gabra2 protein, mouse; D021122:Protein Subunits; D011720:Pyrazoles; D011725:Pyridines; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D045165:Testosterone Congeners; D005680:gamma-Aminobutyric Acid; D000077334:Zolpidem; C034317:tracazolate