ion channels

ion channels cells are enveloped in a lipid membrane that forms a barrier to the diffusion of ionized substances. Ion channels are specialized proteins that sit in the membrane and form aqueous pores, through which ions can flow. Ion fluxes across the cell membrane produce electrical currents, which cause changes in the membrane potential. Cells can generate a rich variety of electrical signals by the opening and closing of different combinations of ion channels. These signals are used for a multitude of different purposes. All of the sensory information we receive from the outside world, whether it be visual, auditory, olfactory, or mechanical, is processed and analysed using electrical signals. Nerve cells use electrical signals of approximately 100 mV in amplitude and 1–2 milliseconds in duration to convey information rapidly over distances of up to 1 m. These signals are called action potentials, and they can travel at rates of up to 120 m/sec without diminishing in size. The heart uses similar electrical signals to regulate the rate and force of the heartbeat. Ions that play a key role in the electrical excitability of nerve and muscle include potassium (K⁺), sodium (Na⁺), calcium (Ca²⁺), and chloride (Cl^-).

Other ion channels found in electrically non-excitable cells have predominantly a transport role. For example, those in the kidneys are important in regulating the levels of salts and water within the body, whereas those in the lungs regulate fluid secretion and absorption — when these channels are absent, as occurs in patients with cystic fibrosis, then the mucous lining of the airways becomes dehydrated.

The opening and closing of ion channels is highly regulated. Different types of channels respond to different stimuli, which can be chemical, electrical, or even mechanical. Those activated by a change in membrane potential are called voltage-activated, whereas those activated by an external chemical ligand (a molecule that binds to them) are called ligand-activated. Ion channels are selectively permeable to different classes of small ions; this is necessary for a channel to generate the electromotive forces needed for electrical signalling. Some ion channels discriminate only between cations and anions, whereas others are highly selective and can discriminate very effectively between ions that are similar. For example, many of the potassium-selective ion channels prefer potassium to sodium by a hundred-fold or more, and despite their discerning nature can conduct 10 000 000 potassium ions across the membrane each second through a single channel molecule. Ions move through the pore passively, and the direction of current flow depends only upon the difference in the internal and external ionic concentration and the potential across the membrane, so when the electrical force and chemical force acting upon an ion are of equal magnitude, but opposite in direction, then there is no current flow across the membrane.

In nerve, muscle, and endocrine cells, electrical signals are translated into a cellular response by the opening of voltage-activated, calcium-selective ion channels. The resting levels of calcium within cells is very low (less than 10^-7 M), and the influx of calcium into the cell causes a rise in the internal concentration. Many cellular processes, including contraction of all types of muscle and the secretion of neurotransmitters and hormones, are regulated by internal calcium. Thus the influx of calcium triggers a response. Internal calcium also controls the ‘gating’ of some ion channels.

The idea that channels form aqueous pores in the membrane began in the 1950s, when Hodgkin and Huxley developed a method for clamping the voltage across the membrane of a giant axon (nerve fibre) taken from a squid, whilst simultaneously measuring the current flow. The large size of the currents suggested that ions must flow through aqueous pores rather than be transported by a carrier mechanism. Hodgkin and Huxley measured inward currents carried by sodium ions and outward currents carried by potassium ions, and showed that these voltage-activated channels underlie the generation of action potentials in axons.

In the late 1970s and early 1980s, Neher and Sakmann developed ‘patch clamp’ recording methods, which enabled very small patches of membrane to be electrically isolated from the rest of the cell membrane. The tip of a glass micropipette (diameter 1 mm) is pressed against the cell and a seal is formed, between the glass and the membrane, which has a resistance of greater than 10⁹ ohms. Currents flowing through single ion channels within the patch of membrane can be recorded, and the opening and closing of the channel is observed as step-wise changes in the current level.

Some of the most important advances in our understanding of ion channels in the last two decades have arisen from the development of recombinant DNA techniques, which have enabled the cloning of genes that encode ion channel proteins. The first ion channels to be purified and cloned were an acetylcholine receptor channel and the voltage-activated sodium channel from the electric organs of the marine ray and electric eel, by Numa and colleagues in the early 1980s. Similar channels were subsequently cloned from mammalian muscle. They are macromolecular complexes composed of several different protein subunits. Well over 100 ion channel genes have now been cloned, and from the predicted amino acid sequences it is clear that there are families of related ion channels that must have arisen from the same ancestral gene by the process of gene duplication and subsequent divergence of the sequence. Similar ion channel structures are found in cells from a wide variety of life forms, including animals, plants, paramecia, and bacteria, indicating that these channels appeared very early on during evolution.

In more recent years, molecular genetics has revealed an increasing number of hereditary diseases that we now know to be caused by mutations in genes that encode ion channels. One of the most well known is cystic fibrosis; others include muscle diseases such as (para)myotonia congenita and hypo- and hyper-kalaemic periodic paralysis. There are also hereditary kidney and heart diseases which are known to be caused by conductance defects. One of the challenges for the future is to develop gene transfer therapies to treat patients with these diseases.

Ruth Murrell-Lagnado

See also cell; cell membrane; genetics, human.