Receptor Desensitization by Neurotransmitters in Membranes:  Are Neurotransmitters the Endogenous Anesthetics?

Abstract

A mechanism of anesthesia is proposed that addresses one of the most troubling peculiarities of general anesthesia: the remarkably small variability of sensitivity within the human population and across a broad range of animal phyla. It is hypothesized that in addition to the rapid, saturable binding of a neurotransmitter to its receptor that results in activation, the neurotransmitter also acts indirectly on the receptor by diffusing into the postsynaptic membrane and changing its physical properties, causing a shift in receptor conformational equilibrium (desensitization). Unlike binding, this slower indirect mechanism is nonspecific: each neurotransmitter will, in principle, affect all receptors in the membrane. For proteins modeled as having only resting and active conformational states, time-dependent ion currents are predicted that exhibit many characteristics of desensitization for both inhibitory and excitatory channels. If receptors have been engineered to regulate the time course of ion currents by this mechanism, then (a) mutations that significantly alter receptor sensitivity to this effect would be lethal and (b) by design, excitatory receptors would be inhibited, but inhibitory receptors activated, so that their effects are not counterproductive. The wide range of exogenous molecules that affect the physical properties of membranes as do neurotransmitters, but that do not bind to receptors, would thus inhibit excitatory channels and activate inhibitory channels, i.e., they would act as anesthesics. The endogenous anesthetics would thus be the neurotransmitters, the survival advantage conferred by their proper membrane-mediated desensitization of receptors explaining the selection pressure for anesthesic sensitivity.

Aromatic Residue Position on the Nonpolar Face of Class A Amphipathic Helical Peptides Determines Biological Activity

“…The concept of lateral pressure profile was developed by Cantor (42) and used initially to explain the action of general anesthetics but has been shown to have applicability to may aspects of membrane structure and function (43). In this description, the lateral interactions in the phospholipid-water interface vary with the depth of penetration of a molecule such as a peptide into the phospholipid milieu.…”

Ion transfer voltammetry of tryptamine, serotonin, and tryptophan at the nitrobenzene/water interface

“…5HT acts as a neurotransmitter in the central nervous system of animals. The interaction between 5HT and phospholipid membranes has become of interest in recent years, and has been studied by calorimetry [1][2][3], fluorometry [4], and theoretical calculations [5,6]. The researchers in this field are requiring a reliable value of the hydrophobicity of the cationic form of 5HT, because 5HT is protonated at physiological pH.…”

First Experimental Evidence of Dopamine Interactions with Negatively Charged Model Biomembranes

“…1,2 Cantor predicted that the neurotransmitters can modulate synaptic transmission by affecting receptor conformational equilibria in a manner similar to anesthetics. 4 The suggested mechanism of anesthetic activity is nonspecific: neurotransmitters can alter conformations of all receptors present in the synaptic membrane. 4 The hypothesis of the possible anesthetic-like activity of neurotransmitters is strongly supported by the results of the whole-cell electrophysiology experiment showing that acetylcholine, glycine, and γ-aminobutyric acid (GABA) modulate the function of receptors for which they are not the native agonist.…”

“…4 The suggested mechanism of anesthetic activity is nonspecific: neurotransmitters can alter conformations of all receptors present in the synaptic membrane. 4 The hypothesis of the possible anesthetic-like activity of neurotransmitters is strongly supported by the results of the whole-cell electrophysiology experiment showing that acetylcholine, glycine, and γ-aminobutyric acid (GABA) modulate the function of receptors for which they are not the native agonist. 5 It is still largely uncertain if anesthetics influence the function of membrane-embedded proteins directly 6 or indirectly by interacting with lipid membranes.…”