Ion Channels: Structure and Function
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. The function of ion channels is typically regulated by a number of signaling molecules.
Section of phospholipid bilayer membrane containing three hypothetic ion channels:
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 determines the specificity of the channel.
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 species is characterized by its ion selectivity sequence: it may be highly specific for a single ion species or it may be less specific, conducting a few or several ion species. 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 regulatory proteins.
Alternatively, ion channels may be involved in non-genetic diseases, e.g. diarrhea, which is mediated by toxicological effects on ion channel function.
Ion channel genes of the human genome
Since the human genome was sequenced at least 400 ion channel structures have been identified of which only about 100 have been cloned and functionally tested. Many genomics companies aim at identifying new ion channels and validating these as novel drug targets. This task requires a significant and focused scientific and technical effort.
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. Typical primary tests are fluorescent-based, directed towards the rapidly increasing number of cloned channels. Active substances from these tests are further analyzed in functional studies. 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 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. Also incorporation of ion channels in artificial lipid bilayers and expression of ion channels in Xenopus oocytes are commonly used for functional ion channel studies.
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