Grant: Operating Grant

Voltage-gated ion channels are responsible for the electrical signals in our central nervous system and for the heart beat. Defects in genes encoding for voltage-gated ion channels lead to severe inherited diseases, which include episodic ataxia I (sporadic discoordination) and LQT syndrome (irregular heart beat). Ion channels are therefore a major drug target, and it is important to achieve a thorough understanding of their structure-function relations. The channels respond to the electrical voltage over the cell wall of e.g. nerve cells and open, in response to higher potentials, a central pore that allows ions to pass through the cell wall between the inside and outside of the cell. The channels are formed of two modules, the voltage-sensor and the pore. It is known that the voltage sensor moves in response to voltage. This movement in turn has to be transferred to pore opening, a process called electromechanical coupling. In this project, we are investigating how this electromechanical coupling is working. The channels consist of four identical units, which are thought to influence each other (cooperativity). We will also investigate the coupling of the four subunits as it is closely related to electromechanical coupling. To achieve our goal, we will investigate modified (mutant) channels using simultaneous electrophysiology and fluorescence spectroscopy (voltage-clamp fluorometry). This technique allows us to visualize the movement in the order of a few Å (10e-10m) of a specific point in the protein and - at the same time - measure the opening of the channel. We can even see the movement (fluorescence) of a single channel so that we can identify how the four identical parts of the channel are coupled to each other. We found several mutations that influence the coupling also to cause the disease episodic ataxia. If we understand the coupling mechanism in detail, we will also be able to define strategies to design drugs to correct abnormal coupling