Why can all of biology be anesthetized?

Abstract

When everything that lives can be immobilized, inhibited, or anesthetized with the same simple compounds, all within roughly a 10-fold concentration range, biology is trying to tell us something important. There are several possibilities for this remarkable degree of conservation, some of which are enumerated in this set of papers, but most boil down to either (a) evolutionary pressure for a specific anesthetic target or targets, or (b) evolutionary pressure for a biological feature that is hijacked by anesthetics. It would seem that no one favors the first notion very strongly, although Professor Sonner suggests an indirect approach to it by proposing that the targets are ion channels accessed via interactions with the lipid membrane.1 He should be applauded for the courage to resurrect this notion, now with a hypothetical linkage that accommodates conservation. In this case, the selection pressure is the need for a means to minimize over-stimulation (excitoxicity, perhaps) using small molecules, essentially an extension of Professor Cantor’s ideas.2 As I understand the model, the transmitter first stimulates the ion channel and then reaches concentrations in the synapse that influence properties of the lipid membrane to exert a form of feedback inhibition on the protein. But, given the extreme degree of degeneracy of molecules that are proposed by Professor Sonner to produce this membrane effect, it seems likely that the organism(s) would have encountered many during evolution. It then becomes difficult to imagine that this degenerate feature, which renders an organism incapable of growing, reproducing or defending itself, could select for anything but elimination. There are, after all, other strategies for feedback inhibition or effect reversal which biology has already used (transporters, catalytic enzymes, feedback circuitry, etc). Professor Morgan’s idea of a feedback control for fermenting organisms is certainly a reasonable possibility.3 But then it is not clear why the selection has remained so strong in organisms that minimally use this sort of biochemistry (mammals), and that have, in fact, become more sensitive instead of less (compared to yeast, for example). Further, despite the similarity when drawn as stick figures, the simple alcohols have very different physicochemical texture as compared to the inhaled anesthetics. It has not yet been shown that they bind the same protein sites as do the inhaled anesthetics, and they probably distribute in lipid membranes differently. So what molecules could have produced the evolutionary pressure, and why has evolution made us more, rather than less, sensitive? The second possibility, raised by both Professor Crowder4 and myself, is the possibility that there are features on or in anesthetic targets (be they protein or lipid - see later) that have other important roles which have been independently selected for, and which the anesthetics hijack to alter function or activity of the target. It seems to me that this is where the money is. And the prime candidate for the selected-for feature is the protein cavity. Protein cavities are essentially packing defects in a protein after it has folded into a three-dimensional structure.5 A slice through almost any protein will reveal a Swiss Cheese-like character, a variety of sizes and shapes of such holes. Occasionally, they contain small molecules, which may or may not be native ligands, but they are often empty, or contain a few water molecules. So why are they there? Surely biology could have figured out how to pack proteins better if cavities were not important. The most likely explanation is that they are there (perhaps, have evolved) to allow protein motion6 or small ligand migration.7 Proteins must be able to move to alter their conformations between active and inactive forms. If they were perfectly packed, this would be very difficult, as the energy required to break the packing, and the time required to create new and perfect packing, would be prohibitive. Cavities allow for these transitions with lower energy requirements. In biophysics-speak, they destabilize the protein structure because of lower contact surface area and allow for easier shifts of side chains and other structural elements because of less steric constraint (i.e., more “elbow room”). That they have been selected for from the very beginning, or more likely, are simply an intrinsic feature of amino acid polymers, is apparent from the fact that all proteins, even of ancient origin, have them.8 Further, a simple analysis of these packing defects has revealed that a very large number of them can readily accommodate molecules the size and shape of anesthetics.9 The diversity in protein cavities matches the enormous range of shapes and sizes of compounds with anesthetic activity, and thus might explain how so many different small molecules can cause anesthesia. Most are hydrophobic, and yet contain the occasional polar residue, and have highly