Structural and functional characterization of the gamma 1 subunit of GABAA/benzodiazepine receptors.
The GABAA receptor gamma 1 subunit of human, rat and bovine origin was molecularly cloned and compared with the gamma 2 subunit in structure and function. Both gamma subunit variants share 74% sequence similarity and are prominently synthesized in often distinct areas of the central nervous system as documented by in situ hybridization. When co-expressed with alpha and beta subunits in Xenopus oocytes and mammalian cells, the gamma variants mediate the potentiation of GABA evoked currents by benzodiazepines and help generate high-affinity binding sites for these drugs. However, these sites show disparate pharmacological properties which, for receptors assembled from alpha 1, beta 1 and gamma 1 subunits, are characterized by the conspicuous loss in affinity for neutral antagonists (e.g. flumazenil) and negative modulators (e.g. DMCM). These findings reveal a pronounced effect of gamma subunit variants on GABAA/benzodiazepine receptor pharmacology.
Ymer
S
S
Laboratory of Molecular Neuroendocrinology, University of Heidelberg, FRG.
Draguhn
A
A
Wisden
W
W
Werner
P
P
Keinänen
K
K
Schofield
P R
PR
Sprengel
R
R
Pritchett
D B
DB
Seeburg
P H
PH
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D002417:Cattle; D003001:Cloning, Molecular; D004247:DNA / Q000235:genetics / Q000302:isolation & purification; D015723:Gene Library; D014644:Genetic Variation; D006801:Humans; D046911:Macromolecular Substances; D008969:Molecular Sequence Data; D009693:Nucleic Acid Hybridization; D015345:Oligonucleotide Probes; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics* / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D012689:Sequence Homology, Nucleic Acid
D046911:Macromolecular Substances; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D011994:Recombinant Proteins; D004247:DNA