Ion channels are targets for selective drugs

Ion channels constitute a large and diverse group of membrane proteins that function as electrical signal transducers, and they govern the electrical properties of all living cells. For example, the coordinated activity of several ion channels is the mechanism underlying action potentials in excitable cells, such as those in the heart and brain.

Ion channels are in general heteromultimeric integral membrane proteins constituting water filled passageways for ions across the phospholipid bilayer membrane. The physical pore is shaped by an assembly of several subunits, and the pore is lined with hydrophilic amino acid residues. A narrow region of the pore is typically charged and constitutes a 'selectivity-filter' that determine which ions can pass through the pore.

Ion channels may open and close in response to membrane potential (voltage-gated ion channels) or chemical (ligand-gated ion channels) stimuli.

Classification of Ion Channels
Each ion channel is characterized by its ion selectivity sequence. It may be highly specific for a single ion  or it may be less specific, conducting a few or several different ions. The selectivity is reflected in the common classification of the channels:

K⁺ channels
Na⁺ channels
Ca²⁺ channels
Cl^- channels
non-selective cation channels

Functionally, ion channels are broadly divided into voltage- and ligand-gated channels, referring to the type of physiological stimulus that activates the channel.

Diseases linked to Ion Channels
A multitude of human and animal diseases are caused by dysfunction of ion channels. This may be genetic, i.e. caused directly by mutations in genes coding for ion channels. Such diseases are called 'channelopathies'. Examples of channelopathies are cystic fibrosis, epilepsy, and cardiac arrhythmias, e.g. the long QT syndrome. Also, diseases may result from defects caused by mutations in genes coding for proteins which regulate ion channels.

Alternatively, ion channels may be involved in non-genetic diseases, e.g. diarrhea, which is mediated by toxicological effects on ion channel function.

Ion channels as drug targets
The search for new, potent and selective drugs that interact with specific ion channels is strongly technology driven and focused on high-throughput screening. Active substances from these high throughput screens are further analyzed in functional studies, such as patch clamp. This development towards screening at the molecular level has been enabled primarily by: 1) the cloning and expression of relevant ion channels in cell lines and 2) novel biological high-throughput screening techniques.

Technologies for ion channel characterization
The only direct way of validating the effect of a chemical entity on an ion channel is to measure the ionic current through the channel and determine whether the compound causes a change in this current. The patch clamp technique (link) has proven extremely useful in revealing many aspects of ion channel function. However, traditional patch clamp has serious shortcomings in pharmaceutical discovery and screening, because the throughput is low, and it requires highly specialized personnel.

With the advent of automated patch clamp equipment these shortcomings are largely abolished. The QPatch allows an operator without prior electrophysiological knowledge to conduct experiments. With the help of the highly skilled application scientists at Sophion, or a skilled electrophysiologist in your staff - you too can be a patch clamper!