5. Ion Channels Flashcards
What does it mean to say that the ion channels of nerve cells are heterogeneous?
In different parts of the nervous system different types of channels carry out specific signalling tasks.
What often results from the malfunctioning of ion channels?
Because of their key roles in electrical signalling, malfunctioning of ion channels can cause a wide variety of neurological diseases.
Why do ion channels play a crucial role in both the normal physiology and pathophysiology of the nervous system?
Ion channels are often the site of action of drugs, poisons, or toxins. Thus ion channels have crucial roles in both the normal physiology and pathophysiology of the nervous system.
In addition to ion channels, nerve cells contain a second important class of proteins with a similar function. What are these?
In addition to ion channels, nerve cells contain a second important class of proteins specialised for moving ions across cell membranes, the ion trans- porters or pumps.
What role do these ion pumps play in neuronal signalling?
These proteins do not participate in rapid neuronal signalling but rather are important for establishing and maintaining the concentration gradients of physiologically important ions between the inside and outside of the cell.
What three important properties do ion channels have?
(1) They recognise and select specific ions
(2) They open and close in response to specific electrical, mechanical, or chemical signals
(3) They conduct ions across the membrane.
What causes the large flow if electric charge during an action potential?
The channels in nerve and muscle conduct ions across the cell membrane at extremely rapid rates, thereby providing a large flow of electric charge. Up to 100 million ions can pass through a single channel each second. This current causes the rapid changes in membrane potential required for signalling
What is a surprising feature of these ion channels given the fast turnover rate?
In light of such an extraordinary rate of ion flow, channels are surprisingly selective for the ions they allow to permeate. Each type of channel allows only one or a few types of ions to pass.
How do ion channels ‘know’ when to open?
Many channels open and close in response to a specific event: Voltage-gated channels are regulated by changes in membrane potential, ligand-gated channels by chemical transmitters, and mechanically gated channels by pressure or stretch. However, some channels are normally open in the cell at rest. The ion flux through these “resting” channels contributes significantly to the resting potential.
How are ion channels limited in a manner in which ion pumps are not?
Ion channels are limited to catalyzing the passive movement of ions down their thermodynamic concentration and electrical gradients. For example, Na+ ions enter a cell through voltage-gated Na+ channels during an action potential because the external Na+ concentration is much greater than the internal concentration; the open channels allow Na+ to diffuse into the cell down its concentration gradient. With such passive ion movement the Na+ concentration gradient would eventually dissipate were it not for
ion pumps.
Name four ions in which ion pumps manage
Different types of ion pumps maintain the concentration gradients for Na+ , K+ , Ca 2+ , Cl- , and other ions.
These pumps differ from ion channels in two important details. Describe these
First, whereas open ion channels have a continuous water-filled pathway through which ions flow unimpeded from one side of the membrane to the other, each time a pump moves an ion, or a group of a few ions, across the membrane, it must undergo a series of conformational changes. As a result, the rate of ion flow through pumps is 100 to 100,000 times slower than through channels.
Second, pumps that maintain ion gradients use energy, often in the form of adenosine triphosphate (ATP), to transport ions against their electrical and chemical gradients. Such ion movements are termed active transport.
Describe the plasma membrane of nerve cells
The plasma membrane of all cells, including nerve cells, is approximately 6 to 8 nm thick and consists of a mosaic of lipids and proteins. The core of the membrane is formed by a double layer of phospholipids. Embedded within this continuous lipid sheet are integral membrane proteins, including ion channels.
How does the lipid membrane differ to that of the ions within and outside in terms of what they attract?
The lipids of the membrane do not mix with water—they are hydrophobic. In contrast, the ions within the cell and those outside strongly attract water molecules—they are hydrophilic.
Why do the ions attract water?
Ions attract water because water molecules are dipolar: Although the net charge on a water molecule is zero, charge is separated within the molecule. The oxygen atom in a water molecule tends to attract electrons and so bears a small net negative charge, whereas the hydrogen atoms tend to lose electrons and therefore carry a small net positive charge. As a result of this unequal distribution of charge, positively charged ions (cations) are strongly attracted electrostatically to the oxygen atom of water, and negatively charged ions (anions) are attracted to the hydrogen atoms. Similarly, ions attract water; in fact they become surrounded by electrostatically bound waters of hydration
What is meant by ‘electrostatic’? **
relating to stationary electric charges or fields as opposed to electric currents.
Can an ion move away from water into the noncharged hydrocarbon tails of the lipid bilayer in the membrane? Why not or how?
An ion cannot move away from water into the noncharged hydrocarbon tails of the lipid bilayer in the membrane unless a large amount of energy is expended to overcome the attraction between the ion and the surrounding water molecules. For this reason it is extremely unlikely that an ion will move from solution into the lipid bilayer, and therefore the bilayer itself is almost completely impermeable to ions.
Why can ion channel selectivity not be based solely on the diameter of the ion?
Selectivity cannot be based solely on the diameter of the ion because K , with a crystal radius of 0.133 nm, is larger than Na+ (crystal radius of 0.095 nm).
How can a water-filled channel conduct ions at high rates and yet be selective? How, for instance, does a channel allow K+ ions to pass while excluding Na+ ions?
Because ions in solution are surrounded by waters of hydration, the ease with which an ion moves in solution (its mobility or diffusion constant) depends on the size of the ion together with the shell of water surrounding it. The smaller an ion, the more highly localised is its charge and the stronger its electric field. As a result, smaller ions attract water more strongly. Thus, as Na+ moves through solution its stronger electrostatic attraction for water causes it to have a larger water shell, which tends to slow it down relative to K .
Because of its larger water shell, Na+ behaves as if it is larger than K+ . In fact, there is a precise relationship between the size of an ion and its mobility in solution: the smaller the ion, the lower its mobility. We therefore can construct a model of a channel that selects K+ rather than Na+ simply on the basis of the interaction of the two ions with water in a water-filled channel
Although this model explains how a channel can select K+ and exclude Na+ , where does it fall short? How has this developed since?
It does not explain how a channel could select Na+ and exclude K+ . Moreover, the model cannot account quantitatively for the very high ionic selectivity exhibited by biological K+ channels.
Even though we now know that ions can cross membranes by means of a variety of transport macro-molecules, the Na -K pump being a well-characterised example, many properties of membrane ion conductances do not fit the carrier model.
What is the most important characteristic of ion channels which is not accounted for in this model? How do we know of this characteristic?
Most important is the rapid rate of ion transfer across membranes. This transfer rate was first examined in the early 1970s by measuring the transmembrane current initiated when the neurotransmitter acetylcholine (ACh) binds its receptor in the cell membrane of skeletal muscle fibers at the synapse between nerve and muscle. Using measurements of membrane current noise, small statistical fluctuations in the mean ionic current induced by ACh, Bernard Katz and Ricardo Miledi concluded that the current conducted by a single ACh receptor is 10 million ions per second. In contrast, the Na+ -K+ pump transports at most 100 ions per second.
What is this rate of transport evidence against?
If the ACh receptor acted as a carrier, it would
have to shuttle an ion across the membrane in 0.1 μs
(one ten-millionth of a second), an implausibly fast
rate. The 100,000-fold difference in rates strongly suggests that the ACh receptor (and other ligand-gates receptors) must conduct ions through a channel.
But we are still left with the problem of what makes a channel selective. How did Bertil Hille explain selectivity?
To explain selectivity, Bertil Hille extended the pore theory by proposing that channels have narrow regions that act as molecular sieves. At this selectivity filter an ion must shed most of its waters of hydration to traverse the channel; in their place weak chemical bonds (electrostatic interactions) form with polar (charged) amino acid residues that line the walls of the channel. Because shedding its waters of hydration is energetically unfavourable, the ion will traverse a channel only if its energy of interaction with the selectivity filter compensates for the loss of the energy of interaction with its waters of hydration. Ions traversing the channel are normally bound to the selectivity filter for only a short time (less than 1 μs), after which electrostatic and diffusional forces propel the ion through the channel. In channels where the pore diameter is large enough to accommodate several water molecules, an ion need not be stripped completely of its water shell.
How is this chemical recognition and specificity of ion channels established? Describe one theory
According to one theory was developed in the early 1960s by George Eisenman, a binding site with a high negative field strength—for example, one formed by negatively charged carboxylic acid groups of glutamate or aspartate — will bind Na+ more tightly than K+. This selectivity results because the electrostatic interaction between two charged groups, as governed by Coulomb’s law, depends inversely on the distance between the two groups.
Because Na has a smaller crystal radius than K , it will approach a negative site more closely than K+ and thus will derive a more favourable free-energy change on binding. This compensates for the requirement that Na+ lose some of its waters of hydration to traverse the narrow selectivity filter. In contrast, a binding site with a low negative strength—one that is composed, for example, of polar carbonyl or hydroxyl oxygen atoms—would select K over Na .
At such a site the binding of Na+ would not provide a sufficient free-energy change to compensate for the loss of the ion’s waters of hydration, which Na+ holds strongly. However, such a site would be able to compensate for the loss of a K+ ion’s associated water molecules as the larger K+ ions interact more weakly with water.