Understanding the impact of the lipid bilayer on ion channel function

Contributed by Sergio Perez Conesa

All our thoughts, movements, and heartbeats are governed by electrical signals in our bodies. These electrical signals are nothing but charged particles, called ions, crossing our cells’ membranes.  The cell membrane is the barrier that marks the inside and the outside of the cell. It is formed by oil-like molecules known as lipids and is mostly an electrical insulator. Nevertheless, conduction can happen because ions are able to cross the membrane through specific pore-like proteins known as ion channels. Ion channels control the flow of electrical signals, acting as switches that respond to stimuli such as pressure, voltage, or specific molecules like neurotransmitters. Defects in ion channels can have severe consequences such as heart arrhythmias or epilepsy. This makes ion channels one of the main targets of pharmaceutical research. 

The cell membrane was once thought to be simply a non-interacting environment, an oily solvent for the proteins in it. Recently the scientific community has learned that the lipids of the membrane act as modulators of ion channels. In our current project we tackle the question: how does the lipid environment influence the behaviour of potassium ion channels? Does the channel conduct more or less current if you change the membrane composition? Will its spontaneous closing (inactivation) be affected? These may seem like basic science questions, but phospholipid-based drugs are potentially a new therapeutic angle to fix malfunctioning ion channels.

In our project 16815 we have set 28 runs each with 1000 clones for 100 generations. All the runs contain a model K-ion channel (KcsA) embedded in a membrane and surrounded with an ionic solution. We study the ion channel KcsA because it is a bacterial ancestor of human potassium channels, which are too big to simulate. In this way, we can infer results for human channels from KcsA in the same way that experiments on rats are extrapolated to humans. Every run contains this same protein but varies the membrane composition. We aim to discover the differences in the channel’s behavior between membrane compositions. The project is 70% done and has already generated 10 Tb of data! Thanks to the FAH donors I have been able to study many more lipids conditions and for much longer timescales than I ever thought possible!