Isoform-specific interactions between halothane and the ryanodine receptorCa2+-release channel: Implications for malignant hyperthermia and the protein theory of anaesthetic action
Gr. Fromming et K. Ohlendieck, Isoform-specific interactions between halothane and the ryanodine receptorCa2+-release channel: Implications for malignant hyperthermia and the protein theory of anaesthetic action, NATURWISSEN, 86(12), 1999, pp. 584-587
General anaesthetics exhibit a relatively close relationship between their
pharmacological potency and their lipid solubility and may thus act by non-
specific perturbation of biomembranes. However, more recent data on anaesth
etic action suggests that inhalational drugs such as halothane bind directl
y to hydrophobic protein domains, thereby modulating important receptor fun
ctions. In support of this protein theory of anaesthetic action our native
gel analysis presented here shows that halothane induces oligomerization of
the skeletal muscle ryanodine receptor (RyR) 1 Ca2+-release channel, but n
ot its cardiac RyR-2 isoform. Thus, inhalational anaesthetics are not only
able to influence protein-protein interactions directly but also appear to
differentiate between protein isoforms and/or configurations. This suggests
that distinct peptide binding sites exist for these pharmacological agents
. In addition, similar mutations in the RyR-2 isoform, which would trigger
an episode of malignant hyperthermia in skeletal muscle fibres via abnormal
RyR-1 isoforms, would probably not induce an increase in cardiac Ca2+-rele
ase upon administration of halothane.