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

One of the most conserved mechanisms for transmission of a nerve pulse across a synapse relies on acetylcholine (ACh). Ever since the Nobel Prize-winning works of Dale and Loewi, it has been assumed that ACh-subsequent to its action on a postsynaptic cell-is split into inactive by-products by acetylcholinesterase (AChE). Herein, the widespread assumption of inactivity of ACh's hydrolysis products is falsified. Excitable cells (Chara braunii internodes), which had previously been unresponsive to ACh, became ACh-sensitive in the presence of AChE. The latter was evidenced by a striking difference in cell membrane depolarization upon exposure to 10 mM intact ACh (∆V = -2 ± 5 mV) and its hydrolysate (∆V = 81 ± 19 mV), respectively, for 60 s. This pronounced depolarization, which also triggered action potentials, was clearly attributed to one of the hydrolysis products: acetic acid (∆V = 87 ± 9 mV at pH 4.0; choline ineffective in the 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 ACh is a most fundamental question that has not been addressed so far.