Biogenesis and control of ion channel composition

Biogenesis of ion channels and molecular machines

The field has made great strides understanding how ion channels open and close, and how they select for one tiny ion, like potassium, over another, like sodium. A new frontier of ion channel biology is the question of how ion channels, which are often made up of multiple subunits, are formed. We have recently discovered that the mRNA transcripts encoding the two subunits that make up cardiac IKr channels are themselves associated in a way that ensures the nascent proteins, while they emerge from the protein-synthesizing machinery, interact with each other.

A bigger question is how the balance of ion channels is achieved to ensure an action potential of the right duration in the heart, or frequency of firing in the brain. There must be mechanisms at multiple levels contributing to this precise control, perturbation of which can lead to diseases such as catastrophic cardiac arrhythmias or epilepsy. We are currently testing the hypothesis that the numbers of different ion channel types, or the “stoichiometry of excitability,” is regulated during channel biogenesis as the proteins are synthesized. For these studies we are using innovative molecular biology approaches, single-molecule fluorescence of mRNA and protein, and patch clamp electrophysiology.