Alcohol and anesthetic action at the gate of a voltage-dependent K+ channel

The role of direct interactions between ion channels and general anesthetic agents, including 1-alkanols, is broadly recognized. Relevant models that may allow direct visualization of these interactions are critical for understanding the molecular bases of general anesthesia and alcohol intoxication. The Drosophila Shaw2 K+ channel is selectively modulated by 1-alkanols at pharmacologically relevant concentrations. From our studies, we have concluded that: (1) amphiphilic interactions control the binding of 1-alkanols to an intracellularly accessible site in the Shaw2 protein; and (2) the modulation (inhibition or potentiation) depends on the secondary structures of the S4-S5 loop and the distal region of the S6 segment, which are components of the main activation gate and may directly contribute to the 1-alkanol binding site. Here, we summarize our work and discuss ideas that may shed light on the structural basis of the modulation of the Shaw2 K+ channel by 1-alkanols.