On the excitation of action potentials by protons and its potential implications for cholinergic transmission

TL;DR

This study challenges the traditional view of cholinergic transmission by showing that protons, produced from acetylcholine hydrolysis, can directly excite cells and trigger action potentials, suggesting a new mechanism for synaptic signaling.

Contribution

It demonstrates that acetylcholine hydrolysis produces protons that can excite cells, proposing a novel role for protons in cholinergic transmission beyond acetylcholine itself.

Findings

Acetylcholinesterase increases cell sensitivity to acetylcholine.

Protons from acetylcholine hydrolysis cause membrane depolarization.

Acetic acid triggers action potentials in excitable cells.

Abstract

One of the most conserved mechanisms for transmission of a nerve pulse across a synapse relies on acetylcholine. Ever since the Nobel-prize winning works of Dale and Loewi, it has been assumed that acetylcholine - subsequent to its action on a postsynaptic cell - is split into inactive by-products by acetylcholinesterase. Herein, this widespread assumption is falsified. Excitable cells (Chara australis internodes), which had previously been unresponsive to acetylcholine, became acetylcholine-sensitive in presence of acetylcholinesterase. The latter was evidenced by a striking difference in cell membrane depolarisation upon exposure to 10 mM intact acetylcholine (deltaV=-2plus/minus5 mV) and its hydrolysate respectively (deltaV=81plus/minus19 mV) for 60 sec. This pronounced depolarization, which also triggered action potentials, was clearly attributed to one of the hydrolysis products: acetic acid (deltaV=87plus/minus9 mV at pH 4.0; choline ineffective in range 1-10 mM). In agreement with our findings, numerous studies in the literature have reported that acids excite gels, lipid membranes, plant cells, erythrocytes as well as neurons. Whether excitation of the postsynaptic cell in a cholinergic synapse is due to protons or due to intact acetylcholine is a most fundamental question that has not been addressed so far.