An absolutely brilliant piece of physical chemistry explained a puzzling biologic phenomenon that organic chemistry was powerless to illuminate.
First, a fair amount of background
Ion channels are proteins present in the cell membrane of all our cells, but in neurons they are responsible for the maintenance of a membrane potential across the membrane, which has the ability change abruptly causing an nerve cell to fire an impulse. Functionally, ligand activated ion channels are pretty easy to understand. A chemical binds to them and they open and the neuron fires (or a muscle contracts — same thing). The channels don’t let everything in, just particular ions. Thus one type of channel which binds acetyl choline lets in sodium (not potassium, not calcium) which causes the cell to fire impulses. The GABA[A] receptor (the ion channel for gamma amino butyric acid) lets in chloride ions (and little else) which inhibits the neuron carrying it from firing. (This is why the benzodiazepines and barbiturates are anticonvulsants).
Since ion channels are full of amino acids, some of which have charged side chains, it’s easy to see how a change in electrical potential across the cell membrane could open or shut them.
By the way, the potential is huge although it doesn’t seem like much. It is usually given as 70 milliVolts (inside negatively charged, outside positively charged). Why is this a big deal? Because the electric field across our membranes is huge. 70 x 10^-3 volts is only 70 milliVolts. The cell membrane is quite thin — just 70 Angstroms. This is 7 nanoMeters (7 x 10^-9) meters. Divide 7 x 10^-3 volts by 7 x 10^-9 and you get a field of 10,000,000 Volts/meter.
Now for the main course. We easily sense hot and cold. This is because we have a bunch of different ion channels which open in response to different temperatures. All this without neurotransmitters binding to them, or changes in electric potential across the membrane.
People had searched for some particular sequence of amino acids common to the channels to no avail (this is the failure of organic chemistry).
In a brilliant paper, entropy was found to be the culprit. Chemists are used to considering entropy effects (primarily on reaction kinetics, but on equilibria as well). What happens is that in the open state a large number of hydrophobic amino acids are exposed to the extracellular space. To accommodate them (e.g. to solvate them), water around them must be more ordered, decreasing entropy. This, of course, is why oil and water don’t mix.
As all the chemists among us should remember, the equilibrium constant has components due to kinetic energy (e.g. heat, e.g. enthalpy) and due to entropy.
The entropy term must be multiplied by the temperature, which is where the temperature sensitivity of the equilibrium constant (in this case open channel/closed channel) comes in. Remember changes in entropy and enthalpy work in opposite directions —
delta G(ibbs free energy) = delta H (enthalpy) - T * delta S (entropy
Here’s the paper [ Cell vol. 158 pp. 977 - 979, 1148 1158 '14 ] They note that if a large number of buried hydrophobic groups become exposed to water on a conformational change in the ion channel, an increased heat capacity should be produced due to water ordering to solvate the hydrophobic side chains. This should confer a strong temperature dependence on the equilibrium constant for the reaction. Exposing just 20 hydrophobic side chains in a tetrameric channel should do the trick. The side chains don’t have to be localized in a particular area (which is why organic chemists and biochemists couldn’t find a stretch of amino acids conferring cold or heat sensitivity — it didn’t matter where the hydrophobic amino acids were, as long as there were enough of them, somewhere).
In some way this entwines enthalpy and entropy making temperature dependent activation U shaped rather than monotonic. So such a channel is in principle both hot activated and cold activated, with the position of the U along the temperature axis determining which activation mode is seen at experimentally accessible temperatures.
All very nice, but how many beautiful theories have we seen get crushed by ugly facts. If they really understood what is going on with temperature sensitivity, they should be able to change a cold activated ion channel to a heat activated one (by mutating it). If they really, really understood things, they should be able to take a run of the mill temperature INsensitive ion channel and make it temperature sensitive. Amazingly, the authors did just that.
Impressive. Read the paper.
This harks back to the days when theories of organic reaction mechanisms were tested by building molecules to test them. When you made a molecule that no one had seen before and predicted how it would react you knew you were on to something.