Trafficking and potential assembly patterns of epsilon-containing GABAA receptors.
Incorporation of the epsilon subunit into the GABAA receptor has been suggested to confer unusual, but variable, biophysical and pharmacological characteristics to both recombinant and native receptors. Due to their structural similarity with the gamma subunits, epsilon subunits have been assumed to substitute at the single position of the gamma subunit in assembled receptors. However, prior work suggests that functional variability in epsilon-containing receptors may reflect alternative sites of incorporation and of not just one, but possibly multiple epsilon subunits in the pentameric receptor complex. Here we present data indicating that increased expression of epsilon, in conjunction with alpha2 and beta3 subunits, results in expression of GABAA receptors with correspondingly altered rectification, deactivation and levels of spontaneous openings, but not increased total current density. We also provide data that the epsilon subunit, like the beta3 subunit, can self-export and data from chimeric receptors suggesting that similarities between the assembly domains of the beta3 and the epsilon subunits may allow the epsilon subunit to replace the beta, as well as the gamma, subunit. The substitution of an epsilon for a beta, as well as the gamma subunit and formation of receptors with alternative patterns of assembly with respect to epsilon incorporation may underlie the observed variability in both biophysical and pharmacological properties noted not only in recombinant, but also in native receptors.
Jones
Brian L
BL
Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.
Henderson
Leslie P
LP
D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology; D046911:Macromolecular Substances / Q000737:chemistry / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000235:genetics; D008958:Models, Molecular; D009433:Neural Inhibition / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000187:drug effects / Q000502:physiology; D021122:Protein Subunits / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D021381:Protein Transport / Q000502:physiology; D011963:Receptors, GABA-A / Q000096:biosynthesis* / Q000737:chemistry / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D009435:Synaptic Transmission / Q000235:genetics; D014162:Transfection; D015032:Zinc / Q000378:metabolism / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism / Q000494:pharmacology
C546274:GABRE protein, human; D046911:Macromolecular Substances; D021122:Protein Subunits; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D005680:gamma-Aminobutyric Acid; D015032:Zinc