Department of Pharmacology and Toxicology

Structure activity studies on ion channels

Electrical excitability in our body is mediated by ion channels. Ion channels are pore forming membrane proteins selectively passing either sodium, potassium, calcium or chloride ions. They occur as large families of related genes with cell-specific expression patterns. Ion channels are important targets for many different classes of drugs such as antiarrhythmics (sodium potassium calcium channels), benzodiazepines (GABA-A channels), local anaesthetics (sodium channels), antihypertensives (calcium channels), antiepileptics (sodium, calcium channels) and many others.

Voltage-gated ion channels open when the membrane potential changes whereas ligand-gated channels open upon interaction with a hormone or neurotransmitter. To understand how ion channels open and close we apply biophysical (two microelectrode voltage clamp, patch clamp technique) and molecular biological techniques (directed mutagenesis). Several disease states are related to dysfunctional ion channels. Among prominent groups are cardiac arrhythmias, diabetes, hypertension, angina pectoris, migraine and epilepsy.

The most interesting questions are still open: Where the gates of ion channels are located? How do ion channels ensure that they stay closed at rest and open during a change in membrane potential or the binding of a neurotransmitter? Where are the binding determinants for the many different drugs are located and how channel block occurs at a molecular level?

Many drugs seem to bind with higher affinity to one of the functional states (open or inactivated) of the channel proteins. This allows the drugs to inhibit channels preferentially when they are in a high activity state, a phenomenon called "use-dependence". Over the past few years our work gave new insights how this feature optimises drug action an how use-dependen ce may occur at a molecular level and ( 1 , 2 , 3 ). Supported by FWF project 15914.