INHIBITION OF PROTEIN-KINASE-C BY ALCOHOLS AND ANESTHETICS

Citation
Sj. Slater et al., INHIBITION OF PROTEIN-KINASE-C BY ALCOHOLS AND ANESTHETICS, Nature, 364(6432), 1993, pp. 82-84
Citations number
29
Categorie Soggetti
Multidisciplinary Sciences
Journal title
NatureACNP
ISSN journal
00280836
Volume
364
Issue
6432
Year of publication
1993
Pages
82 - 84
Database
ISI
SICI code
0028-0836(1993)364:6432<82:IOPBAA>2.0.ZU;2-V
Abstract
DESPITE almost a century of research, the mechanism of anaesthesia rem ains obscure and there is still no agreement on the location of the si te(s) of action1-7. Because the potencies of general anaesthetics incr ease in proportion to their solubility in olive oil, this led to a con sensus that the site is within the cell membrane 8-10. This led to the ories that lipid bilayer perturbation was the primary event, which was then transmitted to a membrane protein11. But at the concentrations u sed clinically, such perturbations are small3. A plausible site would be in or on ion channels at the synapse, where a number of modulatory effects have been described6. A possible location for such a site woul d be at the protein-lipid interface5,12,13. We report here that anaest hetics inhibit protein kinase C, a key component in signal transductio n. The potency is a linear function of the octanol-water partition coe fficient (the Meyer-Overton rule of anaesthesia). The effect was obtai ned in a lipid-free assay, implicating a hydrophobic site in the prote in, supporting the contention that a (membrane) protein may be a targe t for anaesthetic interactions14-17. In a lipid-dependent assay, a pot ential role of lipids in the protein-site model was demonstrated. The inhibition was absent in the isolated catalytic domain, suggesting tha t the site of inhibition is on the regulatory subunit, which is unique to protein kinase C.