Ion Channels

Ions are charged particles such as Na⁺, H⁺, K⁺, Ca²⁺, and Cl⁻. Ions have a significant effect on many cell processes and also influence the amount of water in the cell. Cells use inorganic ions for transmitting signals across the cell membrane or along the surface of the cell. Other cellular functions as diverse as secretion of hormones to fertilization of egg cells require ion transport across the cell membrane. However, ions have great difficulty passing through the membrane by simple diffusion because cell membranes are composed of hydrophobic phospholipids that oppose the passage of hydrophilic ions. Furthermore, the negatively charged phosphate head groups of the phospholipids tend to repel negatively charged anions and trap positively charged cations. Therefore, an ion as small as a hydrogen ion (H⁺) requires a specific portal protein to facilitate its transport through the membrane. Such a protein molecule is called an ion channel.

Molecular Structure of Potassium and Sodium Channels

An ion channel is usually equipped with four basic parts: a central conduction pathway (opening) for ions to pass through, an ion recognition site to allow passage of specific ions (selectivity filter), one or more gates that may open or close, and a sensor that senses the triggering signal and transmits it to the gate.

The Shaker-type voltage-gated potassium channel of nerve and muscle provides a good example of the four parts of the ion channel. The name Shaker arises from the gene coding for this channel in the fruitfly (Drosophila melanogaster ), whose mutation causes the fly to shake. Humans have many potassium channels belonging to the Shaker family. This channel is composed of four identical subunits arranged like a four-leaf clover, with the center serving as the ion conduction pathway. Each subunit has six segments that cross the membrane and are termed S1 through S6. The region between S5 and S6 segments from each subunit contributes to form the ion conduction pathway; hence, it is called the "pore" or "Pregion."

In the P-region, a few critical amino acids from each subunit gather to form the selectivity filter that specifically recognizes only potassium ions. The S4 segment contains positively charged amino acids on every third position and serves as a voltage sensor. When the potential on the internal surface of the membrane becomes more positive, the potential drives the S4 segment toward the outside. This movement triggers a channel gate to open. The voltage-gated sodium channel has a similar architecture, except that the four subunits are strung together in a long peptide chain like a train of parading elephants linking up trunk-to-tail. This channel is highly selective for sodium ions.

Biophysics

As the charged ions flow across the membrane, they generate an electric current. The amount of current flow is determined by three factors. First, when the gate of an ion channel opens, ions flow down the concentration gradient from high to low across the membrane, which is typical of the passive transport mechanism. Second, the flow of ions is controlled by the voltage difference across the membrane. For instance, if the cell interior is already highly positive, less K⁺ will flow in. Third, a channel may be highly selective for a specific ion (such as the voltage-gated sodium channel) or rather nonselective (such as the mechano-sensitive channel). Thus, the total ion flow is influenced by the concentration gradient of the ions, the voltage difference across the membrane, and the permeability of the ions.

The patch clamp technique developed in 1980 has enabled scientists to record current flow through a single ion channel. This technique uses extremely fine glass electrodes attached to membranes to measure electrical activity in a very small part of the membrane. One of the most exciting results from the development of the patch clamp technique is direct observation of the opening and closing of a single channel, like observing the twinkle of a little star in the night sky. The opening of a channel represents a conformational change of the channel molecule from a closed state to an open state. If the rate for such a conformational change is dependent on voltage, then the channel is said to be voltage-gated. A channel may stay in the open state for less than a millisecond to tens of seconds. The current flow through a single channel may range from less than a picoampere to hundreds of picoamperes (a picoampere is 10⁻¹² ampere).

Drugs and Toxins Acting on Ion Channels

Nature produces a wide variety of highly potent toxins that target specific ion channels. The toxins are usually packaged in venom and delivered by stings or fangs. A large number of toxins have been isolated from scorpions, sea anemones, cone snails, and snakes. They have been used for studying various ion channels. One of the most famous toxins is tetrodotoxin, which selectively blocks the sodium channel. It is contained in the poisonous puffer fish, which ironically is the most expensive delicacy served in Japanese restaurants. Only chefs who have passed rigorous licensing examinations are allowed to prepare the fish. Tetrodotoxin is also commonly portrayed in fictions and movies; it almost killed the fictitious Agent 007 James Bond in From Russia with Love. Drugs have been developed to target ion channels and to prevent the channels from conducting ions. They are widely used as local anesthetics, antiarrhythmic drugs to prevent irregular heartbeats, antihypertensive drugs to lower blood pressure, and anti-epileptic drugs to prevent seizures.

Genetic Defects of Ion Channels

Several genetic diseases exhibiting defects in the physiological functions of ion channels have now been shown to be caused by mutations in the genes coding for specific ion channels. For example, a cardiac potassium channel named HERG (human ether-a-go-go-related gene) acts to protect the heart against inappropriate rhythmicity. People lacking a functional HERG gene exhibit an abnormality on their electrocardiogram called "long Q-T syndrome," which predisposes them to sudden cardiac arrest when they are under stress. Cystic fibrosis results from mutations of a particular chloride channel called the cystic fibrosis transmembrane conductance regulator.

see also Membrane Proteins; Membrane Transport; Neuron; Synaptic Transmission

Chau H. Wu

Bibliography

Hille, Bertil. Ionic Channels of Excitable Membranes, 2nd ed. Sunderland, MA: Sinauer Associates Inc., 1992.

Neher, Erwin, and Bert Sakmann. "The Patch Clamp Technique." Scientific American 266 (1992): 44–51.

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

Ion Channels

Ion channels play a fundamental role in the way cells communicate. They generate the electrical signals that make hearts beat and muscles contract, and allow brains to receive and process information. This communication between cells allows for the orchestration of physical and mental activities in humans. Many diseases result from ion channels that do not function properly.

Ion channels are transmembrane proteins that span the cell membrane and are formed from one or more protein subunits. The channels are shaped like tunnels, which form pores through the plasma membrane. The pores have gates that open and close to allow ions to diffuse down their chemical gradient and move in or out of a cell. Ion channels are specific for certain types (and combinations of types) of ions, such as chloride, sodium, potassium, and calcium.

Ions are atoms or molecules that have gained or lost one or more electrons to give them either a net positive or negative electrical charge. They are unequally distributed, creating a separation of charge across a membrane, resulting in an electrical potential. When an ion channel is open, a million ions can flow in or out of the cell per second. This causes an electrical signal or current, which allows cells to communicate very quickly.

There are two major classes of ion channels defined by the way the channel opens: ligand-gated and voltage-gated. Ligand-gated ion channels open when a specific chemical signal called a neurotransmitter is released from one cell, diffuses through a gap known as a synapse, and binds to receptors on ion channels of a second cell. The binding of the neurotransmitter causes the ion channel gate to open. Voltage-gated ion channels have sensors for the electrical potential across the membrane. They open when the cell is at a specific membrane potential. Some other channels can open due to mechanical stress or the levels of signaling molecules inside the cell.

An important function of ion channels is to regulate when cells are at rest and when they are communicating. When a neuron is at its resting potential, it is not sending a signal to any other cells. The inside of a neuron at rest is more negative than the outside. If a neuron is stimulated to communicate with other cells, ion channels open to make the inside of the cell more positive than the resting potential. The neuron will reach a threshold and fire an action potential, where voltage-gated ions channels open, allowing sodium ions to rush in and potassium ions to rush out of the cell. Action potentials propagate and repeat many times to carry a signal the length of a nerve cell. This cell can then continue to communicate by releasing neurotransmitter to bind ligand-gated ion channels on another cell.

A number of diseases occur when ion channels do not function properly. Some examples are epilepsy, cystic fibrosis, heart arrhythmia, and high blood pressure. Ion channels are also the target of many types of drugs and toxins, which can alter the fundamental communication between cells.

see also Concentration Gradient; Membrane; Neurotransmitters; Transmembrane Protein.

Ingrid A. Lobo

R. Adron Harris

Bibliography

Changeux, Jean-Pierre (1993). "Chemical Signaling in the Brain." Scientific American 269(5):58–62.

Keynes, Richard D. (1989). "Synapse Formation in the Developing Brain." Scientific American 240(3):126–132, 134–135.

ion channel A protein that spans a cell membrane to form a water-filled pore through which ions can pass in or out of the cell or cell compartment. Ion channels are found in the plasma membrane and in certain internal cell membranes. They vary in how they open and close and in their selectivity to different ions: some may be specific for one particular ion, whereas others may admit two or more similar ions (e.g. K⁺ and Na⁺). The electrical and chemical environment inside cells, including the resting potential, is determined largely by the numbers, types, and activity of the cell's ion channels; they play a crucial role in the excitability of nerve and muscle cells. Ions pass through their respective channels at a rate and in a direction dictated mainly by the electrochemical gradients across the membrane. Ungated ion channels are permanently open, whereas gated ion channels can open and close. Of the latter there are two main types: ligand-gated ion channels, which typically open when a signal molecule binds to a receptor region of the channel protein, and voltage-gated ion channels, which respond to changes in membrane potential.