Ball-and-Chain Inactivation in Potassium Channels

Carefully orchestrated opening and closing of ion channels control the diffusion of ions across cell membranes, generating the electrical signals required for fast transmission of information throughout the nervous system. Inactivation is a parsimonious means for channels to restrict ion conduction without the need to remove the activating stimulus. Voltage-gated channel inactivation plays crucial physiological roles, such as controlling action potential duration and firing frequency in neurons. The ball-and-chain moniker applies to a type of inactivation proposed first for sodium channels and later shown to be a universal mechanism. Still, structural evidence for this mechanism remained elusive until recently. We review the ball-and-chain inactivation research starting from its introduction as a crucial component of sodium conductance during electrical signaling in the classical Hodgkin and Huxley studies, through the discovery of its simple intuitive mechanism in potassium channels during the molecular cloning era, to the eventual elucidation of a potassium channel structure in a ball-and-chain inactivated state.