A transmembrane residue influences the interaction of propofol with the strychnine-sensitive glycine alpha1 and alpha1beta receptor.
BACKGROUND
Propofol, well known for its anesthetic effects, acts as a positive allosteric modulator of the alpha-aminobutyric acid type A (GABA(A)) receptor but also enhances the function of the glycine receptor. The GABA modulatory effects of propofol are influenced by an amino acid residue located within the second transmembrane domain (TM2) of the GABA(A) receptor beta subunit. In glycine alpha(1) subunits, the homologous residue (serine 267) affects the glycine modulatory actions of alcohols and alkane anesthetics. In the present study we investigated the role of this residue on the interaction of propofol with the glycine alpha(1) and alpha(1)beta receptor.


METHODS
The influence of propofol on wild type and mutant (alpha(1)S267M, alpha(1)S267I, alpha(1)S267Mbeta, alpha(1)S267Ibeta) glycine receptors expressed in human embryonic kidney 293 cells was investigated by using the whole-cell clamp technique.


RESULTS
Mutation of the alpha(1) subunit TM2 serine residue to either isoleucine or methionine decreased the sensitivity of the receptor to glycine, and abolished the direct activation of the glycine receptor by propofol. Additionally, the methionine and particularly the isoleucine mutation decreased the glycine-enhancing actions of propofol.


CONCLUSIONS
The nature of the TM2 residue (267) of the glycine alpha(1) subunit influences the glycine modulatory effect of propofol and direct activation of the receptor by this anesthetic. A comparison of the impact of such complementary mutations on the interaction of propofol with glycine and GABA(A) receptors should permit a better understanding of the molecular determinants of action of propofol on these structurally related receptors and may aid in the development of selective glycine receptor modulators.
Ahrens
Jörg
J
Department of Anesthesiology, OE 8050, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany. ahrens.j@mh-hannover.de
Leuwer
Martin
M
Stachura
Sina
S
Krampfl
Klaus
K
Belelli
Delia
D
Lambert
Jeremy J
JJ
Haeseler
Gertrud
G
D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D002478:Cells, Cultured; D006801:Humans; D016297:Mutagenesis, Site-Directed; D015742:Propofol / Q000494:pharmacology*; D011963:Receptors, GABA-A / Q000737:chemistry / Q000187:drug effects; D018009:Receptors, Glycine / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000494:pharmacology*
D018686:Anesthetics, Intravenous; C114561:GLRB protein, human; D011963:Receptors, GABA-A; D018009:Receptors, Glycine; D013331:Strychnine; D015742:Propofol