A propofol binding site on mammalian GABAA receptors identified by photolabeling.
Propofol is the most important intravenous general anesthetic in current clinical use. It acts by potentiating GABAA (γ-aminobutyric acid type A) receptors, but where it binds to this receptor is not known and has been a matter of some debate. We synthesized a new propofol analog photolabeling reagent whose biological activity is very similar to that of propofol. We confirmed that this reagent labeled known propofol binding sites in human serum albumin that have been identified using X-ray crystallography. Using a combination of protiated and deuterated versions of the reagent to label mammalian receptors in intact membranes, we identified a new binding site for propofol in GABAA receptors consisting of both β3 homopentamers and α1β3 heteropentamers. The binding site is located within the β subunit at the interface between the transmembrane domains and the extracellular domain and lies close to known determinants of anesthetic sensitivity in the transmembrane segments TM1 and TM2.
1] Department of Life Sciences, Imperial College, London, UK. [2].
Grace M S
GM
Yip
Zi-Wei
ZW
Chen
Christopher J
CJ
Edge
Edward H
EH
Smith
Robert
R
Dickinson
Erhard
E
Hohenester
R Reid
RR
Townsend
Karoline
K
Fuchs
Werner
W
Sieghart
Alex S
AS
Evers
Nicholas P
NP
Franks
D001665:Binding Sites; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D019920:Photoaffinity Labels / Q000032:analysis* / Q000737:chemistry; D015742:Propofol / Q000737:chemistry / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000737:chemistry* / Q000378:metabolism*; D012709:Serum Albumin / Q000737:chemistry; D013329:Structure-Activity Relationship
D019920:Photoaffinity Labels; D011963:Receptors, GABA-A; D012709:Serum Albumin; D015742:Propofol