Ion channels

Author: Prof. Dr. med. Peter Altmeyer

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Last updated on: 29.10.2020

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(e ) Ion channels; Ion channel

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Ion channels are protein complexes (channel proteins or tunnel proteins) consisting of several subunits that form a ring-shaped transmembrane "pore" through the cell membrane. Ion channels are essential for cell function because the cell membrane consists of a hydrophobic lipid bilayer. This layer is almost impassable for ions.

Ion channel and receptor are part of the same protein complex. The receptor is embedded in the cell membrane and consists of 5 subunits which enclose a central pore (ion channel). The binding sites for the endogenous agonist (see figure for a nicotinic acetylcholine receptor) are located extracellularly on one of the channel units. The nicotinic acetylcholine receptor increases the conductivity for Na+ and K+ ions.

In order to enable the passage of ions out of or into cells after activation by an endogenous or exogenous agonist, these special protein complexes are formed which enclose pores (ion channels). The number of ion channels per cell is estimated at102 to104 . This large number per cell reflects the great importance of ion channels for the physiological function of a cell. In the ion channels, the ions flow at high speeds, almost as fast as in free diffusion: up to108 ions per second can be channelled through a single channel!

Channel switching behavior (gating): Ion channels can change their transport rate by specific conformational changes. They are able to switch between the "open" and "closed" states. This property is called channel switching behavior (gating). Gating is controlled by various stimuli, e.g. by:

  • changes in the membrane voltage,
  • Change of transmitter concentrations,
  • mechanical forces such as tension or compression or
  • Changes in temperature (heat or cold).

The switching behaviour of ion channels allows a rapid change in the electrical current through a cell membrane in response to external stimuli. It is the basis of cellular electrical signals.

When the channel is opened, ions can flow along their specific concentration gradient either from the extracellular space into the cytosol or in the opposite direction.

Many cation channels have a high selectivity for a specific type of ion. This is also expressed in their names, e.g. sodium, calcium or potassium channel.

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Depending on the control of their function, four ion channels are distinguished:

  • Voltage dependent ion channels
  • Receptor controlled ion channels
  • G-protein-directed ion channels
  • Second messenger controlled ion channels

Voltage-dependent ion channels open and close the channel pore depending on the level of the membrane potential. Voltage-dependent Na+ channels generate inward currents and are responsible for the formation and conduction of action potentials in excitable cells. Ion channels are also often named after their selectivity: potassium, sodium, calcium or chloride channels.

For example, local anaesthetics are substances that reversibly block the initiation and conduction of action potentials in nerve fibres by blocking voltage-dependent Na+ channels. An intact chloride conductivity is essential for maintaining the function of the retina (Edwards et al., 2010). Thus, mutations in the Clcn2 gene are associated with photoreceptor degeneration (Bosl et al., 2001) and Clcn3 knockout mice show a complete loss of photoreceptors. Structurally, these chloride channels of the ClC family consist of a dimer (Dutzler et al., 2002), i.e. two subunits form a functional unit.

  • Voltage-dependent Na+ channels generate inward currents and ensure the conduction of action potentials in excitable cells.
  • Voltage-dependent K+ channels generate outward currents and ensure the repolarization of the cell membrane after an action potential as well as a sufficiently negative resting membrane potential.

  • Voltage-dependent Ca++ channels produce inward currents, which result in action potentials for some cells, but provide Ca2+ ions inside the cell for others. They occur ubiquitously. A distinction is made between:

    • High-voltage-activated (HVA) channels
    • Low-voltage-activated (LVA) channels (see also blocker)
    • HVA require a high threshold potential for their activation, as opposed to the LVA channels with a low threshold potential.
  • Another classification distinguishes five types of Ca2+ channels:
    • T-Channel (T stands for transient current "and tiny conductance")
    • L-channel (L stands for long-lasting and "large Conductance")
    • N channel (L stands for neither T-nor L)
    • P/Q channel (similar to the N channels, P/Q has no meaning of its own, it was simply counted alphabetically) (Graefe KH 2016)
    • The L-type Ca2+ channel is present in the human organism in smooth muscles (e.g. in the walls of blood vessels), in the cardiovascular system and also in neurons. In smooth muscles and heart muscles, the "long-lasting calcium channels", which allow a slow inflow of calcium into the cell in case of depolarization of the cell membrane, are essential for electromechanical coupling. Calcium antagonists, also called L-channel blockers, are important therapeutics in cardiovascular diseases: diltiazem type, verapamil type, nifedipine type.

Voltage-independent ion channels: Certain ion channels (cation channels) can be activated by various stimuli independent of voltage. These include intracellular factors (e.g. ATP, pH or Ca2+), associated proteins, mechanical tension, thermal stimuli (heat or cold) can be opened or closed by small molecule pore blockers such as Mg2+ or spermine.

  • Receptor-controlled channels act as effector systems for specific receptors (ionotropic receptors). Examples of such channels are the nicotinic acetylcholine receptor and the glutamate receptor of the NMDA type.
  • G-protein controlled channels represent effector systems for the beta/gamma unit of G-proteins. These include K+ channels that are opened by the activation of G-protein-coupled receptors and voltage-dependent Ca2+ channels that are closed by the activation of G-protein-coupled receptors.
  • Second messenger-controlled channels are channels whose function is controlled by intracellular messenger substances such as cAMP, CGMP, Ca2+ and ATP. These channels include the voltage-dependent Ca2+ channels in heart muscle cells. Other examples are the K+ channels which are opened (i.e. activated by high intracellular Ca2+ concentrations) or closed (i.e. sensitive to ATP) by intracellular ATP and which perform a kind of rectifier function in many cells.
  • Mechanosensitive ion channels can be activated by mechanical stimuli (e.g. pressure, vibrations). The mechanoelectric coupling in the inner ear (labyrinth) has been best investigated. At the tip of the stereocilia of the hair cells there is a non-selective cation channel, which is permeable mainly for K+, but also for Ca2+. Acoustic oscillations lead to a deflection of the cilia bundles and via a so-called tip link to the mechanical channel opening. Thus, the cell is depolarized and forms a receptor potential. A deflection in the opposite direction leads to the closure of the channel.
  • Light gated channels, e.g. the channelrhodopsins, are activated by light of a specific wavelength.
  • Temperature-controlled ion channels are activated at a specific temperature.
  • HCN channels, also known as "pacemaker" channels, play an important role in the control of rhythmic electrical excitation because they determine the frequency. Since hyperpolarization and cyclic nucleotides have a decisive influence on the activity of these ion channels, they are also called HCN channels.
  • TRP channels: TRPML2, the abbreviation stands for "Transient Receptor Potential Mucolipin", is an ion channel of the Mucolipin subfamily of TRP channels, which are relevant for sensory perception in humans. Among other things, TRPML2 plays a role in the immune response to infections and increases the infectivity of zika and dengue viruses.

General information
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Ion channels, as an integral part of cell membranes, are essential for the normal function of all cells. For the physiologically relevant Na+/ K+/ Ca2+/ Cl- ions there are concentration gradients between intra- and extracellular space, which are maintained by membrane pumps such as the sodium-potassium pump (ion pumps). Diseases caused by mutation-related malfunctions of ion channels (see below ion channel diseases) are found, for example, in cardiac arrhythmia, epileptic syndromes, neuropathic pain syndromes, certain forms of migraine, myotonic muscle diseases, cystic fibrosis and various nephrogenic tubulopathies.

There is a variety of drugs that are effective through interaction with ion channels. For example, local anaesthetics, Ca2+ channel blockers, anticonvulsants, K+ channel openers, K+ channel blockers.

Clinical picture
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Clinical examples of pathologies of ion channels:

Potassium channel: The importance of an intact potassium channel results from the following casuistry: An 82-year-old female patient is admitted to hospital with pneumonia. She is first treated with the antibiotic erythromycin. After improvement of the symptoms and stabilization of the general condition, the antibiotic clarithromycin is used. After two applications of clarithromycin, the patient first develops ventricular extrasystoles, later ventricular flutter and then ventricular fibrillation. The emergency situation could be eliminated by defibrillation. The cause of this ADR was a mutation of a protein of the potassium channel in the heart. The mutated channel was blocked by the antibiotic clarithromycin, resulting in the disturbed excitation of the myocardium.

Voltage-controlled sodium channel Nav1.7: An 8-year-old Pakistani boy frequently inflicted wounds, pierced his arms with needles and knives, and walked over glowing coals - without feeling any pain. In the village surroundings of this boy, other children between the ages of six and 14 years old were found, who also showed no pain at all. They showed numerous haematomas, poorly healed fractures and injuries to lips and tongue. Sensation of touch, proprioception or temperature perception of these children was normal. Genetic analyses revealed mutations in a gene (SCN9A) coding for a voltage-controlled sodium channel (Nav1.7) expressed in the pain-conducting spinal nerve fibres as the cause of the children's complete insensitivity to pain.

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Ion currents are measured with a glass pipette with an opening that is a thousandth of a millimeter small. The pipette is pressed onto the membrane of the muscle cell. A microscopically small patch is aspirated and the electrical voltage is clamped in place. The membrane section is thus electrically insulated. If there are ion channels in this area, it is possible to measure the duration and magnitude of the current when a channel is opened.

Ion transport proteins: Ion transport proteins in the cell membranes are divided into pumps and channels. A prominent example of an ion pump is the Na+-K+ pump, which transports Na+ ions out of the cell and K+ ions in, while consuming energy (cleavage of ATP) and against the concentration gradient. Ion channels, on the other hand, always conduct ions along their electrochemical gradient, i.e. in the direction of concentration or charge equalization. No energy is required for this form of transport ("facilitated diffusion"). Most ion channels only allow certain ions to pass through (selectivity). They are usually closed when at rest. They are opened by an external stimulus.

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  1. Dutzler R et al (2002) X-ray structure of a ClC chloride channel at 3.0 A reveals the molecular basis of anion selectivity. Nature 415: 287-294.
  2. Edwards MM et al (2010) Photoreceptor degeneration, azoospermia, leukoencephalopathy, and abnormal RPE cell function in mice expressing an early stop mutation in CLCN2. Invest Ophthalmol Vis Sci 51: 3264-3272.
  3. Ertel EA et al (2000) Nomenclature of voltage-gated calcium channels. Neuron 25: 533-535.
  4. Feldbauer K et al (2009) Channelrhodopsin-2 is a leaky proton pump. Proceedings of the National Academy of Sciences USA 106, 12317-12322 (2009).
  5. Pelletier L et al (2018) Involvement of ion channels in allergy. Curr Opin Immunol 52:60-67.
  6. Velge-Roussel F et al (2018) Editorial overview: Ion channels and immunecells: What ions could do for immune cells. Curr Opin Immunol 52:vi- viii.


Last updated on: 29.10.2020