“The King is dead”: Checkmating ion channels with tethered toxins

The quickest possible checkmate in the game of chess requires two moves using a pawn and the queen. Metaphorically speaking, the pawn (a membrane tether) and the queen (a toxin) work together to checkmate an ion channel within a neuronal circuit. This strategy termed “tethered toxin” (t-toxin) is based on the use of genetically encoded peptide toxins that are anchored to the cell-membrane via a glycolipid or transmembrane tether. Because of their mode of action at the cell surface, t-toxins act only on ion channels and receptors of the cell that is expressing the t-toxin, and not on identical receptors present in neighboring cells that do not express the t-toxin. In this mini-review we discuss the design of these genetic tools and their application for cell-specific and temporal manipulation of ion channel-mediated activities in vivo.