Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.
The study of ion channels often involves biophysics, electrophysiology, and pharmacology, while using techniques including voltage clamp, patch clamp, immunohistochemistry, X-ray crystallography, fluoroscopy, and RT-PCR. Their classification as molecules is referred to as channelomics.
Basic features
There are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins: The rate of ion transport through the channel is very high (often 106 ions per second or greater). Ions pass through channels down their electrochemical gradient, which is a function of ion concentration and membrane potential, "downhill", without the input (or help) of metabolic energy (e.g. ATP, co-transport mechanisms, or active transport mechanisms). Ion channels are located within the membrane of all excitable cells, and of many intracellular organelles. They are often described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through. This characteristic is called selective permeability. The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as sodium or potassium. However, some channels may be permeable to the passage of more than one type of ion, typically sharing a common charge: positive (cations) or negative (anions). Ions often move through the segments of the channel pore in a single file nearly as quickly as the ions move through the free solution. In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force.
Ion channels are integral membrane proteins, typically formed as assemblies of several individual proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer. For most voltage-gated ion channels, the pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on.
Biological role
Because channels underlie the nerve impulse and because "transmitter-activated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, numerous toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g., the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails, and others) work by modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as cardiac, skeletal, and smooth muscle contraction, epithelial transport of nutrients and ions, T-cell activation, and pancreatic beta-cell insulin release. In the search for new drugs, ion channels are a frequent target.
Diversity
There are over 300 types of ion channels just in the cells of the inner ear. Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, the number of gates (pores), and localization of proteins.
Further heterogeneity of ion channels arises when channels with different constitutive subunits give rise to a specific kind of current. Absence or mutation of one or more of the contributing types of channel subunits can result in loss of function and, potentially, underlie neurologic diseases.
Classification by gating
Ion channels may be classified by gating, i.e. what opens and closes the channels. For example, voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel.Ravna, A.W., Sylte, I. (2011). Homology Modeling of Transporter Proteins (Carriers and Ion Channels). In: Orry, A., Abagyan, R. (eds) Homology Modeling. Methods in Molecular Biology, vol 857. Humana Press. https://doi.org/10.1007/978-1-61779-588-6_12
Voltage-gated
Voltage-gated ion channels open and close in response to membrane potential. Voltage-gated sodium channels: This family contains at least 9 members and is largely responsible for action potential creation and propagation. The pore-forming α subunits are very large (up to 4,000 amino acids) and consist of four homologous repeat domains (I-IV) each comprising six transmembrane segments (S1-S6) for a total of 24 transmembrane segments. The members of this family also coassemble with auxiliary β subunits, each spanning the membrane once. Both α and β subunits are extensively glycosylated. Voltage-gated calcium channels: This family contains 10 members, though these are known to coassemble with α2δ, β, and γ subunits. These channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are equally large. Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. Voltage-gated potassium channels (KV): This family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane following action potentials. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as tetramers to produce a functioning channel. Some transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: classical (TRPC), vanilloid receptors (TRPV), melastatin (TRPM), polycystins (TRPP), mucolipins (TRPML), and ankyrin transmembrane protein 1 (TRPA). Hyperpolarization-activated cyclic nucleotide-gated channels: The opening of these channels is due to hyperpolarization rather than the depolarization required for other cyclic nucleotide-gated channels. These channels are also sensitive to the cyclic nucleotides cAMP and cGMP, which alter the voltage sensitivity of the channel's opening. These channels are permeable to the monovalent cations K+ and Na+. There are 4 members of this family, all of which form tetramers of six-transmembrane α subunits. As these channels open under hyperpolarizing conditions, they function as pacemaking channels in the heart, particularly the SA node. Voltage-gated proton channels: Voltage-gated proton channels open with depolarization, but in a strongly pH-sensitive manner. The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells. Another important function occurs in phagocytes (e.g. eosinophils, neutrophils, macrophages) during the "respiratory burst." When bacteria or other microbes are engulfed by phagocytes, the enzyme NADPH oxidase assembles in the membrane and begins to produce reactive oxygen species (ROS) that help kill bacteria. NADPH oxidase is electrogenic, moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically.
Ligand-gated (neurotransmitter)
Also known as ionotropic receptors, this group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of such channels include the cation-permeable nicotinic acetylcholine receptors, ionotropic glutamate-gated receptors, acid-sensing ion channels (ASICs), ATP-gated P2X receptors, and the anion-permeable γ-aminobutyric acid-gated GABAA receptor.
Ion channels activated by second messengers may also be categorized in this group, although ligands and second messengers are otherwise distinguished from each other.
Lipid-gated
This group of channels opens in response to specific lipid molecules binding to the channel's transmembrane domain typically near the inner leaflet of the plasma membrane. Phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid (PA) are the best-characterized lipids to gate these channels. Many of the leak potassium channels are gated by lipids including the inward-rectifier potassium channels and two pore domain potassium channels TREK-1 and TRAAK. KCNQ potassium channel family are gated by PIP2. The voltage activated potassium channel (Kv) is regulated by PA. Its midpoint of activation shifts +50 mV upon PA hydrolysis, near resting membrane potentials. This suggests Kv could be opened by lipid hydrolysis independent of voltage and may qualify this channel as dual lipid and voltage gated channel.
Other gating
Gating also includes activation and inactivation by second messengers from the inside of the cell membrane – rather than from outside the cell, as in the case for ligands. Some potassium channels: Inward-rectifier potassium channels: These channels allow potassium ions to flow into the cell in an "inwardly rectifying" manner: potassium flows more efficiently into than out of the cell. This family is composed of 15 official and 1 unofficial member and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular ATP, PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as pacemaker activity in the heart, insulin release, and potassium uptake in glial cells. They contain only two transmembrane segments, corresponding to the core pore-forming segments of the KV and KCa channels. Their α subunits form tetramers. Calcium-activated potassium channels: This family of channels is activated by intracellular Ca2+ and contains 8 members. Tandem pore domain potassium channel: This family of 15 members form what are known as leak channels, and they display Goldman-Hodgkin-Katz (open) rectification. Contrary to their common name of 'Two-pore-domain potassium channels', these channels have only one pore but two pore domains per subunit. Two-pore channels include ligand-gated and voltage-gated cation channels, so-named because they contain two pore-forming subunits. As their name suggests, they have two pores. Light-gated channels like channelrhodopsin are directly opened by photons. Mechanosensitive ion channels open under the influence of stretch, pressure, shear, and displacement.