The movement of ions across the cell membrane is essential for many biological processes, such as the transfer of signals through neurones, the stimulation of skeletal muscle and the production of healthy mucus. As with all small molecules, ions can either move across the cell membrane down their concentration gradient (through facilitated diffusion) or against it (through active transport). The lipid bilayer is impermeable to ions and so they must rely on transport proteins to move them across the cell membrane. These transport proteins can be grouped into several different types: ion channels, carrier proteins and ion pumps.
All ion transporting proteins have a membrane spanning region mostly composed of α-helices. These are made up of amino acids with hydrophobic side chains which stick out of the side of the helix and anchor the protein to the lipid membrane through hydrophobic interactions. The hydrophilic peptide groups are on the inside of the protein, allowing ions to lose their water shell when entering the protein and form electrostatic interactions with the peptide groups instead.
These move ions down their concentration gradient and are the fastest type of transport protein as they do not need to undergo a conformational change. Ion channels can be highly selective (e.g. only transporting Na+ ions) or more general, such as allowing through any cation. There are two main types of ion channels: gated and non-gated. Non-gated channels, such as the K+ channels involved in maintaining resting potential in neurones, allow ions through at all times, provided there is a concentration gradient for them to move down. Gated channels will only ‘open’ under the correct circumstances, such as a certain membrane potential (voltage gated channels) or when an activating ligand binds to the channel (ligand gated channels).
How can ion channels be so specific?
Ion channels rely partly on the size of ions (ionic radius) to determine which ion can pass through them- e.g. Na+ ions are smaller than K+ ions and the Na+ ion channel pore is too small for K+ ions to pass through easily. However, this is little use for distinguishing between ions of a similar radius such as Na+ and Ca2+ or for K+ channels, as the smaller Na+ ions could easily fit through the pore in a K+ channel. Instead, channels use a selectivity filter to determine which ion can pass through the pore. This is a series of a few, highly conserved, amino acids at the entrance to the pore, one on each subunit (e.g. in K+ channels the selectivity filter is the series Thr-Val-Gly-Tyr-Gly).
When ions enter a channel pore they must first lose their shell of water molecules and form new electrostatic interactions with the oxygen atoms of the carbonyl groups in the selectivity filter. It requires energy for an ion to lose its water shell so this will only happen if the new interactions it forms are more energetically favourable. In the case of the K+ channel, the oxygen atoms of the selectivity filter are ideally positioned to form interactions with K+ ions but not with Na+ ions as they are too small. This makes it energetically unfavourable for Na+ ions to enter a K+ channel and so it is very unlikely to occur.
Voltage gated channels
These contain voltage sensing α helices made up of positively charged amino acid residues (each third residue has a positively charged side chain). When the channel is closed, the positively charged α helices are attracted to the negative charges on the cytosolic side of the membrane, keeping the channel in a closed conformation, with the ‘gate’ segment of the protein blocking the channel pore.
When the cytosol becomes more positive (such as during depolarisation of a neurone), the voltage sensing α helices are repelled and move towards the exoplasmic side of the membrane, inducing a conformational change in the gate segment of the ion channel and allowing ions to move through the pore. After a very short amount of time (0.5-1.0ms for Na+ channels, slightly longer for K+ channels), the voltage sensing helices return to their original position and the channel inactivating segment moves to block the pore. After repolarisation has taken place and the membrane is back to its resting potential, the channel inactivating segment is displaced and the channel returns to its original conformation.
Ligand gated channels
As with most ion channels, ligand gated channels are usually very highly specific for one or two particular species of ion, e.g. the acetylcholine receptor at neurone synapses which transports Na+ and K+ ions. Acetylcholine diffuses across the synapse and then binds to the extracellular domain of the receptor, which induces a conformational change in the ion channel so that ions can pass through it. This conformational change is believed to be the rotation of α helices within the channel pore so that the large hydrophobic residues that were previously facing into the pore are replaced by small hydrophilic residues which can interact with the ions and allow them to move through the channel.
These can transport many different types of small molecules, not just ions and they are much slower than channels as they undergo a conformational change every time they move a molecule across the lipid bilayer. (Carrier proteins transport molecules/ion at a rate of 1-1000 per second whereas ion channels transport ions at up to 10^8 per second) There are three main types of carriers:
• Uniporters- move one molecule at a time, using facilitated diffusion
• Symporters- move two types of molecule in the same direction simultaneously, e.g. the Na+/glucose symporter.
• Antiporters- transport one type of molecule in one direction while moving another in the opposite direction
Symporters and antiporters use secondary active transport: the movement of one type of molecule down its concentration gradient is used to power the transport of another molecule against its concentration gradient.
These use primary active transport to move ions against their concentration gradient. The energy required to do this is gained by the hydrolysis of ATP, which is used to drive a conformational change in the pump and to push the ion/molecule to the other side of the membrane. Pumps can be divided into four categories, three of which are used exclusively for ion transport.
- P-class pumps- these transport all types of ions, although each type of pump is specific to only one or two kinds of ions. They are composed of two α subunits and sometimes two regulatory β subunits. P-class pumps use the hydrolysis of ATP to pump ions by forming a phosphorylated intermediate which results in a conformational change. Some P-class pumps can transport more than one type of ion at a time, e.g. the Na+/K+ pump. Other examples include the Ca2+ pump found in the sarcoplasmic reticulum and the H+ pump in the plasma membrane of plants, fungi and bacteria.
- V-class pumps- These only transport protons and do not form a phosphoprotein intermediate like P-class proteins. They have a very different structure to P-class pumps, with at least 13 subunits, all of which are unconnected to the subunits in P-class pumps. V-class pumps are normally used to maintain a low pH in vacuoles and lysosomes.
- F-class pumps- these are very similar to V-class pumps in that they only transport protons and do not form a phosphoprotein intermediate. They also have similar structures. However, F-class pumps transport protons down their electrochemical gradient, using the movement of the protons to power ATP synthesis, such as the ATP synthase pump found in mitochondria.
- ABC (ATP Binding Cassette) superfamily pumps- this is a very diverse class of pumps which can transport all kinds of molecules, including polysaccharides and proteins. All pumps in the ABC superfamily contain two transmembrane domains and two cytosolic domains which bind ATP. ABC pumps are found in both prokaryotic and eukaryotic organisms and are needed for many essential functions in the human body, e.g. the CFTR pump in the membrane of epithelial cells, which can cause cystic fibrosis if mutated.
- Huettner, J. (2012) Ion channels. Encyclopedia Britannica. http://www.britannica.com/EBchecked/topic/374288/ion-channel accessed 24/04/2012
- Prakash, S. (2011) Ion channels and their inhibitors. Springer Publishing.
- Chung, S., Anderson, O., Olaf, S., Krishanmurphy, V. (2007) Biological membrane ion channels. Springer Publishing.