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

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.