Ion channels are protein complexes , located in the cell membranes, that regulate vital processes such as the heartbeat or the transmission of signals between neurons.

In this article we will explain what they consist of, what their function and structure is, what kinds of ion channels exist and their relationship to various diseases.

What is an ion channel?

We understand by ion channels protein complexes full of water pores, which let the ions pass through, making them flow from one side to the other of the cell membrane. These channels are present in all cells, of which they are an essential component.

Each cell is surrounded by a membrane that separates it from the outside environment. Its lipid bilayer structure is not easily permeable to polar molecules such as amino acids or ions. Therefore, it is necessary to transport these substances into and out of the cell by means of membrane proteins as pumps, transporters and ion channels.

The channels are made up of one or more different proteins called subunits (alpha, beta, gamma, etc.). When several of them come together, they create a circular structure in whose centre there is a hole or pore, which allows the passage of ions.

One of the particularities of these channels is their selectivity; that is, they determine the passage of some inorganic ions and not others , depending on the diameter and distribution of their amino acids.

The opening and closing of ion channels is regulated by various factors; a specific stimulus or sensor determines that they fluctuate from one state to another by altering their composition.

Now let’s see what functions they perform and what their structure is.

Functions and structure

Behind essential cellular processes, such as the secretion of neurotransmitters or the transmission of electrical signals, are the ionic channels, which confer electrical and excitable capacities to the cells . And when they fail, numerous pathologies can occur (which we will discuss later).

The structure of the ion channels is in the form of transmembrane proteins and act as a gate system to regulate the passage of ions (potassium, sodium, calcium, chlorine, etc.) through pores.

Until a few years ago it was thought that the pores and the voltage sensor were coupled through a linker (a spiral of about 15 amino acids), which can be triggered by the movement of the voltage sensor. This coupling mechanism between the two parts of the ion channel is the canonical mechanism that has always been theorized.

Recently, however, new research has revealed another pathway that involves an amino acid segment made up of part of the voltage sensor and part of the pore . These two segments would be adjusted as a kind of zipper to trigger the opening or closing of the channel. In turn, this new mechanism could explain recent discoveries, in which some voltage-regulated ion channels (some responsible for functions such as the heartbeat) have been detected with only one linker.

Voltage-regulated ion channels are only one type of channel, but there are more: let’s see what they are.

Ion channel types

The mechanisms for the activation of the ion channels can be of various types: by ligand, by voltage or by mechanically sensitive stimuli.

1. Liganding-regulated ion channels

These ion channels open in response to the binding of certain molecules and neurotransmitters . This opening mechanism is due to the interaction of a chemical (which can be a hormone, a peptide or a neurotransmitter) with a part of the channel called the receptor, which generates a change in the free energy and modifies the conformation of the protein by opening the channel.

The nicotinic receptor of acetylcholine (a neurotransmitter involved in the transmission of signals between motor nerves and muscles) is one of the most studied ligand regulated ion channels. It is composed of 5 subunits of 20 amino acids and is involved in basic functions such as the voluntary control of movement, memory, attention, sleep, alertness or anxiety .

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2. Voltage regulated ion channels

These types of channels open in response to changes in electrical potential across the plasma membrane . Voltage regulated ion channels intervene in the transmission of electrical impulses, generating action potentials due to changes in the difference of electrical charges on both sides of the membrane.

The ion flow takes place in two processes: activation, a voltage-dependent process: the channel opens in response to changes in membrane potential (electrical potential difference on both sides of the membrane); and inactivation, a process that regulates the closing of the channel.

The main function of voltage-regulated ion channels is the generation of action potentials and their propagation . There are several types and the main ones are:

2.1. Na+ channel

They are transmembrane proteins that allow the passage of sodium ions through the cell. Ion transport is passive and only depends on the electrochemical potential of the ion (it does not require energy in the form of ATP molecules). In neurons, the sodium channels are responsible for the upward phase of the action potential (depolarization).

2.2. K+ channel

These ion channels constitute the most heterogeneous group of structural membrane proteins. In neurons, depolarization activates K+ channels and facilitates the output of K+ from the nerve cell, leading to repolarization of the membrane potential.

2.3. Ca++ channel

Calcium ions promote the fusion of the synaptic vesicle membrane (structures located at the end of the neuronal axon and responsible for secreting neurotransmitters) with the terminal axon membrane in the neuron, stimulating the release of acetylcholine into the synaptic cleft by a mechanism of exocytosis .

2.4. Cl-channel

This type of ion channel is responsible for regulating cell excitability, transport between cells, as well as PH and cell volume management. Channels located in the membrane stabilize the membrane potential in excitable cells. They are also responsible for the transport between cells of water and electrolytes .

3. Ionic channels regulated by mechanically sensitive stimuli

These ionic channels open in response to mechanical actions . They can be found, for example, in the Paccini corpuscles (sensory receptors in the skin that respond to rapid vibrations and deep mechanical pressure), which open by stretching the cell membrane by applying tension and/or pressure.

Canalopathies: pathologies associated with these molecules

From a physiological point of view, the ionic channels are fundamental for the homeostatic balance of our organism . Their dysfunction causes a whole series of diseases, known as canalopathies. These can be produced by two types of mechanisms: genetic alterations and autoimmune diseases.

Among the genetic alterations, there are the mutations that occur in the coding region of the gene for an ion channel. These mutations usually produce polypeptide chains that are not correctly processed and are not incorporated into the plasma membrane; or, when the subunits are coupled and form the channels, they are not functional.

Another frequent possibility is that, even though they are functional channels, they end up showing altered kinetics. Whatever the case, they usually lead to the gain or loss of channel function.

Also mutations can occur in the promoter region of the gene that codes for an ion channel . This can cause under- or over-expression of the protein, resulting in changes in the number of channels, which would also cause an increase or decrease in its functionality.

At present, multiple pathologies associated with ion channels in different tissues are known. At the musculoskeletal level, mutations in the voltage-activated Na+ , K+ , Ca++ and Cl- channels and in the acetylcholine channel lead to disorders such as hyper- and hypocalytic paralysis, myotonia, malignant hyperthermia and myasthenia .

At the neuronal level, it has been proposed that alterations in the voltage-activated Na+ channels, the voltage-activated K+ and Ca++ channels, the acetylcholine-activated channel or the glycine activated channel, could explain disorders such as epilepsy, episodic ataxia, familial hemiplegic migraine, Lambert-Eaton syndrome, Alzheimer’s disease, Parkinson’s disease and schizophrenia.

Bibliographic references:

  • J. T. Menéndez, “Los poros y los canales iónicos regulan la actividad celular,” in Anales de la Real Academia Nacional de Farmacia, 2004, p. 23.
  • Ana I. Fernández-Mariño, Tyler J. Harpole, Kevin Oelstrom, Lucie Delemotte and Baron Chanda. “Gating interaction maps reveal a noncanonical electromechanical coupling mode in the Shaker K+ channel”. Nature Structural & Molecular Biology 25: 320-326, April 2018.
  • G. Eisenman and J.A. Dani Annu (1987). An introduction to molecular architecture and permeability of ion channels. Rev. Biophys. Biophys. Chem, 16. pp. 205-226.
  • Aidley, D. J. (1989) The physiology of excitable cells. Cambridge University Press.