Physics or Pharmacy?
Next time you go to the hospital for a surgery of any kind, don’t be afraid and ask to your doctor or anesthesiologist: "Could you tell me the anesthetic you will use in the surgery? Surely, one or the other will tell you the name of the drug, although very probably they will not know how the substance acts. Never mind, write it somewhere and once at home, type it on Google. You will find that the anesthetic inhibits sodium channels if it is local and GABA, GlyR, Glutamate channels (among some others) if it is general. In short: type the name of the drug and the literature in the internet will tell you the channel it inhibits.
Inhibition means that the function of such channels is affected (the flow of sodium or calcium ions going into neuron cells is reduced). How? Nobody knows.
Physics sheds a bit of light: if we consider a receptor of a given channel (for example NMDAR) in a neuron cell, water molecules around it and of course ions, what the anesthetic does is to reduce the free energy of the system. And the larger is such reduction, the higher is the specificity; which is proportional to exp(-free energy change/thermal energy).
However:
Free energy can be reduced if the enthalpy decreases or the entropy increases. If the first dominates (enthalpic binding), the interaction is driven by hydrogen bond forces, if the second dominates (entropic binding), the interaction is driven by dispersion forces.
If you type the name of an anesthetic in this page: http://www.chemspider.com/ , the first thing you will discover is that it is hydrophobic: the logarithm of the partition coefficient is positive. Why? Because it likes oil more than water. This simple fact implies that anesthetics interact through dispersion forces (entropic bindings). This is the reason why the more anesthetics dissolve in olive oil, the less is the dose used by the anesthesiologist.
Our dilemma is the following: how this entropic binding inhibit ion channels if inhibition is related to a specific target?
We work in several projects in order to answer the above question:
Local being general
Hundreds of substances posess anesthetic action. However, despite decades of research and tests, a golden rule is required to reconcile the diverse hypothesis behind anesthesia. What makes an anesthetic to be local or general in the first place? We have recently shown that the protonation rate could disentangle the riddle. Read more here.
Cell motility under stress
Recently, we designed a device to measure the motility of cells in a temperature controlled environment. We then study how the cells behave with anesthetics, calcium, caffeine, pH, pressure, and, of course, temperature.
Cellular protection
To understand the above effects, we decided to make it very simple using the noblest anesthetic of all: Xenon, chemically inert, perfectly spheric, very pure, etc. We found something amazing: instead of being an anesthetic (at least at the doses we tried), Xe is a cellular protector. Why? Again, stay tuned.
Noble gases are anesthetics?
The actual paradigm says they inhibit calcium channels. But inhibition requires an enthalpic binding! What noble gases do in a neuron, we believe, is to increase the entropy of the cell membranes, in the same way they do it in a vesicle. See here.
Membrane permeability
Ok, according to the paradigm, ions need channels to go inside cells. But why pure lipid membranes at their melting point permit ion diffusion?
Action potentials or solitons?
What is first, the chicken or the egg? Are you aware that the action potential travels with a soliton? The first produces the second, or viceversa? We are doing experiments to find out. See here.
Lipid rafts and anesthesia
Is the clue of anesthesia in the lipid rafts? We are extracting lipid rafts from rat brains to understand. We recently found that Pentobarbital modifies the stability of lipid rafts reducing the NMDAR and GABAA. Stay tuned.
Why neurotransmitters need Calcium to work?
Put neurotransmitters and lipid vesicles together and nothing happens. Add calcium and bingo: some neurotansmitters behave like anesthetics! And in real neurons? See here.
Are Molecular Dynamic Simulations useful to understand real processes?
We think so, with simulations we can learn a lot. See here.
Giant pure vesicles are intriguing
We are in the way to make giant vesicles and do experiments with anesthetics.
Levitating Bacteria
We collaborate in a project that aims to study biofilms in acoustic levitation. Stay tuned.