Ion channels

Ion channels are integral membrane proteins that form aqueous (water-filled) macromolecular membrane-spanning pores in the plasma membrane. They are involved in the generation and propagation of nerve impulses, synaptic transmission, muscle contraction, salt balance and hormone release.

The advantages of ion channel transport

* High selectivity for specific ion species (substrate specificity).

* The ability to be gated. The gating mechanism is a regulatory system controlling the opening and closing of gates in ion channels. Gating is a process of transition through open (conducting), closed and inactive states accompanied by conformational changes in the ion channels. Forward and backward rate constants for the transitions determine the likelihood of the various channel states.

* The ability to allow very large ion fluxes in short time periods, i.e. a very high catalytic power to substantially increase the flow rate of ions over the free diffusion rate in water.

Ion channel flow rates

The rate of ion flow through an open ion channel depends on: The concentration gradient across the plasma membrane. The voltage gradient across the plasma membrane.

The conductance of the ion channels, which is expressed in units of charge/ second per volt. A high conductance channel allows more ionic flow for a given driving voltage than a low conductance channel. Opening may lead to either inward current generation, leading to depolarisation; outward current generation, leading to hyperpolarisation; or increased conductance, leading to stabilisation of membrane potential.

Closure may lead to either switching off of the inward current, leading to hyperpolarisation; switching off of the outward current, leading to depolarisation; or reduced conductance, leading to increased sensitivity of the cell to other components.

£ Classification of ion channels

3 Ion channels are classified according to their electrophysiological properties, s io drug sensitivity, and by molecular cloning.

y * Ligand (agonist)-gated ion channels (direct-coupled; G-protein-coupled; sec ond messenger-coupled), which include acetylcholine receptors (muscle (nicotinic); neural), glycine receptors, GABA A receptors and glutamate receptors.

* Calcium channels are present in cell membranes in smooth muscle, cardiac muscle and other tissues, and in cellular organelle membranes such as the sarcoplasmic reticulum and mitochondria. Calcium functions as a primary generator of the cardiac action potential and as an intracellular second messenger. Calcium channels are further subdivided into three subgroups based on their threshold for activation and on the spread of inactivation:

L-type (long-lasting): slowly inactivating; high threshold calcium conductance; sensitive to dihydropyridines; involved in excitation-contraction coupling in smooth and cardiac muscle (where they carry current in the plateau phase of the action potential), and in excitation-secretion coupling in endocrine cells and in some neurons. T-type (transient): low voltage activated, rapidly inactivated. N-type (neuronal): transient, high threshold calcium conductance; blocked by omega-conotoxin

The T and L channels are located in smooth and cardiac muscle tissue, whereas the N channels are located only in neuronal tissue.

Calcium channel blockers interact with the L-type calcium channel and consist of four classes of drugs: the 1,4-dihydropyridine derivatives (nifedipine, nimodipine, amlodipine), the phenylalkyl-amines (verapamil), the benzothiaze-pines (diltiazem), and a diarylaminopropylamine ether (bepridil).

* Potassium channels are tetrameric and composed of four identical peptide subunits (alpha subunits) that are symmetrically arranged to form a conical pore that spans the cell membrane. Many potassium channels also contain auxiliary proteins, beta subunits, that may alter electrophysiological or biophysical properties, expression levels or expression patterns. They are divided into:

Six transmembrane-helix voltage-gated channels, which are activated by membrane depolarisation. Two transmembrane-span G-protein-coupled inward rectifying channels, which favour the influx rather than efflux of potassium ions. Calcium-activated channels, which are sensitive to intracellular calcium concentrations:

Large conductance: blocked by charybdotoxin and iberiotoxin; Small conductance: blocked by apamin.

Leak channels, with an apparent lack of gating control. 5

* Sodium channels are discrete, four domain, transmembrane glycoprotein 3

e complexes. Each complex consists of four alpha subunits around the central channel and a beta 1 and beta 2 subunit peripherally. n

DNA cloning has identified three types in central neurons (I, II and III), m1 in g skeletal muscle, and h and I in cardiac muscle. s

Sodium channels are blocked by tetrodotoxin (produced by puffer fish), geo- g graphotoxin and by lipid-soluble amines used as local anaesthetic agents. They are activated by ciguatoxins, pyrethrin and low molecular weight polypeptide toxins from scorpions and sea anemones.

* Chloride channels play an important role in stabilisation of the membrane potential, regulation of cell volume, transepithelial transport and secretion of fluid from secretory glands.

Activation of chloride channels can be achieved by:

Extracellular ligands

Intracellular calcium

Cyclic AMP


Mechanical stretch

Cell swelling

Transmembrane voltage

Methods for the study of ion channel structure

Physical conformation

High resolution electron microscopy; Electron diffraction;

Molecular structure

Isolation of channel proteins by biochemical methods; Molecular cloning to determine amino acid sequences of proteins; Site-directed mutagenesis to alter sequences at selected sites; Expression of channel proteins in host cells, e.g. Xenopus oocytes.

Ion channel disorders

Calcium channels: malignant hyperthermia Chloride channel: cystic fibrosis

Sodium channels: Liddle's syndrome (aldosterone-activated sodium channels in the collecting ducts) Mutant sodium channels: long QT syndrome; Brugada syndrome Potassium channels: isolated deafness syndrome

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