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Ion Channel Linked Receptors

Introduction

There are several methods that cells can use to interpret the signals which are sent to them. Often this involves a chemical sent from one cell, or from the extracellular matrix (the ligand), binding to a specific receptor displayed on the cell surface. There are thousands of specific receptor and ligand combinations and some are specific to certain cell types. One such subset are the ion channel-linked receptors, also called transmitter-gated ion channels, ligand-gated ion channels or ionotropic receptors. These receptors are involved in controlling the flow of ions into cells, and are opened in response to signals from nerve cells.

Ion channel signalling

The purpose of the ion channel-linked receptors is, as the name suggests, to control the flow of ions (charged particles) across cell membranes. They are found on cells which respond to neurotransmitters released from a nerve cell. The ion channel-inked receptors control the flow of ions into a cell and are responsible for converting a chemical signal to an electrical one.

The ions in question are numerous but are most commonly sodium (Na+) or potassium (K+). The ions normally exist in a pool outside of the cell and cannot enter through the plasma membrane.

Ion channel linked receptors are found at synapses - that is, the space between a nerve cell and the cell it is signalling to. In a resting cell, the channels exist in a "closed" conformation, meaning that the ions cannot travel through them.

Ion channel-linked receptors belong to the cys-loop superfamily of receptors. All the channels in this family have five subunits (pentameric) which form a pore through the membrane. Each individual subunit spans the membrane four times. Each transmembrane section is termed M1 to M4. The M2 subunit is the most important subunit for gating - it contains an alpha helix which controls the opening and closing of the gate (Figure 2).

When a signal needs to be transmitted across the synpase, one cell, the presynaptic nerve cell, will release a neurotransmitter - such as acetylcholine - via exocytosis. The postsynaptic cell lies on the other side of the synapse and expresses the ion-channel linked receptors on its surface. When the neurotransmitter binds to the receptor, the channel opens and the ions outside the cell can now enter the cytoplasm of the postsynaptic cell. This affects the cell's internal electrical charge and will produce a response in the postsynaptic cell, for example, other channels may open in response.

Note: Unlike voltage-gated receptors, ion channel-linked receptors are not responsive to the changes in electrical potential within a cell. Ion channel-linked receptors are only opened by neurotransmitters.

 

Figure 1: Ion channel-linked receptors



Ion channel-linked receptor example: acetylcholine receptor

One of the best studied ion channel-linked receptors is the nicotinic acetylcholine receptor (nACh receptor). This is expressed in skeletal muscle cells and has an important function at the neuromuscular junction, helping with muscle contraction.

The channel is opened by the neurotransmitter acetylcholine, released from a nearby neuron. When acetylcholine binds to the receptor, which is expressed on the surface of the muscle cell, the gate in the receptor opens and allows the ions sodium (Na+) and potassium (K+) to enter the cell. This causes the muscle cell to undergo depolarisation due to the change in the electrical potential of the cell. This change in the cell causes other channels, which are sensitive to the cell's electrical state (called voltage-gated ion channels) to open. The end-stage of this process is that voltage-gated calcium (Ca2+) channels are stimulated to open, thus leading to muscle contraction.

Like all members of the cys-loop superfamily of ion-channel-linked receptors, the acetylcholine receptor consists of five subunits: two alpha subunits, and a beta, gamma and delta subunit. The five subunits form a ring with a water-filled pore spanning the plasma membrane (see Figure 2). Each subunit contains an M2 alpha-helix which spans the membrane. In the ACh receptor, these helices contain negatively charged amino acids, such as glutamate or aspartate, at each end. This negative charge prevents negatively charged ions (anions) from passing through the channel.

In the "closed" state of the receptor (no ligand bound), these helices point inwards, blocking the channel and stopping ions from passing through (Figures 2c, 3a). Two acetylcholine molecules are required to bind to the receptor for it to open. When the acetylcholine binds, the helices rotate away from the centre of the channel. This causes the channel to open and the positively charged ions can enter the cell (Figures 2c, 3c). However, even when the ligand is bound, the channel switches between its open and closed states, meaning there is also a chance (about 10%) that the receptor will have the ligand bound, but will be closed (Figure 3b). This "occupied and closed" state will also occur if the levels of acetylcholine are high for a very long period of time - in this case, the channel will deactivate itself (also called desensitisation).

The signal for the channel to open is ended when the acetylcholine no longer occupies the receptor. This is acheived by the hydrolysis of acetylcholine by the enzyme acetylcholinesterase. The channel will then return to its closed (resting) state.

Figure 2: Nicotinic acetylcholine receptors



Figure 3: Different states of the acetylcholine receptor



Other ion channel-linked receptors

Each of these receptors are part of the cys-loop superfamily of receptors. They contain the characteristic five-subunit structure which form a pore through the plasma membrane. However, the channels can be exclusive to different ions - those which let in positive ions (cations) are usually excitatory (they continue the nerve signal), those which let negative ions (anions) through the pore are usually inhibitory (they stop the nerve signal).

Neurotransmitters are very complex, and stimulate several types of receptor. Often one neurotransmitter can activate several different receptors. These receptors are not always ion channel-linked. The most common alternative receptor type is the G-protein coupled receptor (GPCR).

Other ion-channel-linked receptors include:

  • GABA(A) receptor: Opens in response to the neurotransmitter gamma-aminobutyric acid (GABA).  The pore allows negative charged chloride ions (Cl-) into the cell. They are expressed throughout the central nervous system (CNS) and have an inhibitory effect on nerve signalling. This is not to be confused with the G-protein coupled receptor GABA(B).

 

  • Strychnine-sensitive glycine receptor: Opens in response to glycine. This also allows anions through the channel and so is inhibitory.

 

  • Serotonin 5-HT3 receptor: Opens in response to serotonin, also known as 5-HT. 5-HT3 is the only serotonin receptor which is an ion channel-linked receptor, the others are G-protein coupled receptors. The channel linked to the serotonin receptor is an excitory channel, meaning that the channel allows cations (positively charged ions such as sodium, potassium and calcium) through the plasma membrane and this activates the post-synaptic cell, thus carrying on the nerve signal.

 

References

Textbooks:

  • Alberts et al, (2002) "Molecular Biology of the Cell", 4th Edition. Garland Science
  • Lodish et al, (2003) "Molecular Cell Biology" 5th Edition W.H. Freeman

Papers:

  • Bellili and Lambert (2005) "Neurosteroids: Endogenous inhibitors of the GABA(A) receptor". Nature Reviews Neuroscience 6: 565-575
  • Barnes et al (2009) "The 5-HT3 receptor - the relationship between structure and function." Neuropharmacology 56: 273-284
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