A new naturally occurring GABA(A) receptor subunit partnership with high sensitivity to ethanol.
According to the rules of GABA(A) receptor (GABA(A)R) subunit assembly, alpha4 and alpha6 subunits are considered to be the natural partners of delta subunits. These GABA(A)Rs are a preferred target of low, sobriety-impairing concentrations of ethanol. Here we demonstrate a new naturally occurring GABA(A)R subunit partnership: delta subunits of hippocampal interneurons are coexpressed and colocalized with alpha1 subunits, but not with alpha4, alpha6 or any other alpha subunits. Ethanol potentiates the tonic inhibition mediated by such native alpha1/delta GABA(A)Rs in wild-type and in alpha4 subunit-deficient (Gabra4(-/-)) mice, but not in delta subunit-deficient (Gabrd(-/-)) mice. We also ruled out any compensatory upregulation of alpha6 subunits that might have accounted for the ethanol effect in Gabra4(-/-) mice. Thus, alpha1/delta subunit assemblies represent a new neuronal GABA(A)R subunit partnership present in hippocampal interneurons, mediate tonic inhibitory currents and are highly sensitive to low concentrations of ethanol.
Glykys
Joseph
J
Interdepartmental PhD Program for Neuroscience and Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, California 90095, USA.
Peng
Zechun
Z
Chandra
Dev
D
Homanics
Gregg E
GE
Houser
Carolyn R
CR
Mody
Istvan
I
D000818:Animals; D001640:Bicuculline / Q000031:analogs & derivatives / Q000494:pharmacology; D001921:Brain / Q000166:cytology; D002492:Central Nervous System Depressants / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000431:Ethanol / Q000494:pharmacology*; D005665:Furosemide / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D007150:Immunohistochemistry / Q000379:methods; D066298:In Vitro Techniques; D007395:Interneurons / Q000187:drug effects*; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal / Q000379:methods; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques / Q000379:methods; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*; D049994:Sodium Potassium Chloride Symporter Inhibitors / Q000494:pharmacology
D002492:Central Nervous System Depressants; D018756:GABA Antagonists; D007527:Isoenzymes; D011963:Receptors, GABA-A; D049994:Sodium Potassium Chloride Symporter Inhibitors; D000431:Ethanol; C017069:bicuculline methiodide; D005665:Furosemide; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D001640:Bicuculline