HALOTHANE ACTS ON MANY POTASSIUM CHANNELS, INCLUDING A MINIMAL POTASSIUM CHANNEL

There has been considerable controversy over whether general anestheti cs act directly on membrane proteins. and if so, whether there are uni quely sensitive protein targets upon which they act. Here. we examine the actions of halothane on a diverse collection of voltage-gated pota ssium channels expressed in Xenopus oocytes, and find that they are al l sensitive at clinically relevant concentrations. To investigate furt her the molecular basis of this commonality, human and rat minimal pot assium (minK) channels, which have exceedingly short amino acid sequen ces. were examined. Current through these channels is reversibly reduc ed to 68% of control values by 0.5% (0.34 mM) halothane. A double dele tion mutant of the 130-amino acid minK protein, in which 30 amino acid s of the N-terminus, thought to be extracellular, and 37 amino acids o f the putative intracellular C-terminus are deleted (resulting in a pr otein in which more than half of both the extracellular and intracellu lar domains have been removed) responds to low halothane concentration s similarly to the parent channel. While alternative explanations are possible. this result is consistent with a model whereby halothane int eracts with the channel protein from within the lipid bilayer.