A tyrosine kinase regulates propofol-induced modulation of the beta-subunit of the GABA(A) receptor and release of intracellular calcium in cortical rat neurones.
Propofol, an intravenous anaesthetic, has been shown to interact with the beta-subunit of the gamma-amino butyric acid(A) (GABA(A)) receptor and also to cause changes in [Ca2+]i. The GABA(A) receptor, a suggested target for anaesthetics, is known to be regulated by kinases. We have investigated if tyrosine kinase is involved in the intracellular signal system used by propofol to cause anaesthesia. We used primary cell cultured neurones from newborn rats, pre-incubated with or without a tyrosine kinase inhibitor before propofol stimulation. The effect of propofol on tyrosine phosphorylation and changes in [Ca2+]i were investigated. Propofol (3 microg mL(-1), 16.8 microM) increased intracellular calcium levels by 122 +/- 34% (mean +/- SEM) when applied to neurones in calcium free medium. This rise in [Ca2+]i was lowered by 68% when the cells were pre-incubated with the tyrosine kinase inhibitor herbimycin A before exposure to propofol (P < 0.05). Propofol caused an increase (33 +/- 10%) in tyrosine phosphorylation, with maximum at 120 s, of the beta-subunit of the GABA(A)-receptor. This tyrosine phosphorylation was decreased after pre-treatment with herbimycin A (44 +/- 7%, P < 0.05), and was not affected by the absence of exogenous calcium in the medium. Tyrosine kinase participates in the propofol signalling system by inducing the release of calcium from intracellular stores and by modulating the beta-subunit of the GABA(A)-receptor.
Björnström
K
K
Department of Anaesthesiology, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Sjölander
A
A
Schippert
A
A
Eintrei
C
C
D000818:Animals; D016227:Benzoquinones; D002118:Calcium / Q000378:metabolism*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D047029:Lactams, Macrocyclic; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism*; D015742:Propofol / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011809:Quinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects / Q000378:metabolism*; D012016:Reference Values; D017828:Rifabutin / Q000031:analogs & derivatives
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D011809:Quinones; D011963:Receptors, GABA-A; D017828:Rifabutin; C020754:herbimycin; D011505:Protein-Tyrosine Kinases; D002118:Calcium; D015742:Propofol