A transmembrane residue influences the interaction of propofol with the strychnine-sensitive glycine α1 and α1β receptor

J Ahrens, M Leuwer, S Stachura, K Krampfl… - Anesthesia & …, 2008 - journals.lww.com
J Ahrens, M Leuwer, S Stachura, K Krampfl, D Belelli, JJ Lambert, G Haeseler
Anesthesia & Analgesia, 2008journals.lww.com
BACKGROUND: Propofol, well known for its anesthetic effects, acts as a positive allosteric
modulator of the α-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 β subunit. In glycine α 1 subunits, the homologous residue (serine 267) affects
the glycine modulatory actions of alcohols and alkane anesthetics. In the present study we …
BACKGROUND:
Propofol, well known for its anesthetic effects, acts as a positive allosteric modulator of the α-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 β subunit. In glycine α 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 α 1 and α 1 β receptor.
METHODS:
The influence of propofol on wild type and mutant (α 1 S267M, α 1 S267I, α 1 S267Mβ, α 1 S267Iβ) glycine receptors expressed in human embryonic kidney 293 cells was investigated by using the whole-cell clamp technique.
RESULTS:
Mutation of the α 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 α 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.
IMPLICATIONS: Exchange of a single amino acid residue at the α 1 glycine receptor subunit decreases the sensitivity of the receptor to propofol. These results provide the prerequisites for creation of glycine receptor knockin mice clarifying the contribution of glycine receptors to the antinociceptive actions of propofol.
Lippincott Williams & Wilkins