The On-Off Mechanisms of the Nicotinic Acetylcholine Receptor Ion Channel are Performed by Thermodynamic Forces

Abstract

The active sites of nicotinic acetylcholine receptors are comparatively strong hydrophobic areas. When nicotinic acetylcholine receptor α-subunits bind with acetylcholines, the polar groups of nicotinic acetylcholine receptors and acetylcholines become more hydrophobic owing to repulsion of the bound water molecules, and the charged groups of nicotinic acetylcholine receptors and acetylcholines are neutralized. Thus, the large hydrophobic areas form at and around the binding sites of nicotinic acetylcholine receptors and acetylcholines. These exposed hydrophobic areas are unstable thermodynamically (oil in water), and thus sink toward the neighboring hydrophobic transmembrane segment (M2). The sinking of the acetylcholine-binding sites with the M2, which contains an ion channel, causes the negative residues of the top of the M2 to descend to the hydrophilic level of the immobile M2 of the other nicotinic acetylcholine receptor subunits. This pathway, which consists of the hydrophilic part of the sunken α-subunits and the hydrophilic part of the immobile M2 of other subunits, allows for the easy passage of cations across the cellular membrane. The movements of the α-subunits sinking to the transmembrane area cause the release of acetylcholines from binding sites. The hydrophilic groups of acetylcholines (quaternary ammonium ion, etc) and nicotinic acetylcholine receptors (ionic groups of M2, etc) are unstable in hydrophobic conditions (water in oil), resulting in the binding site and the hydrophilic residues of M2 returning to the positions in the resting state. These mechanisms, which we call the "rotation model" (Goto, 1983, Tohoku J. expl Med. 139, 159-164) not only explain various phenomena, including the swelling of excitable cells at the expression of cellular functions, but also predict various as yet unobserved phenomena, including the increase in internal pressure of the excitable cells during functional expression.