The evolution of ACh and GABA as neurotransmitters: a hypothesis.

The development of a signaling system requires the evolution of a mechanism for producing signals, receptors and adaptive reactions to the signal. It is reasonable to assume that the evolution of such a system cannot be the consequence of a coordinated set of mutations resulting in a complete signaling system. It is more likely that each component evolved due to an advantage that was independent of its role in the signaling system. We hypothesize how the neurotransmitters acetylcholine (ACh) and gamma-aminobutyric acid (GABA) evolved gradually, from an initial stage in which the efflux of these molecules from the cell was an inevitable consequence of specific metabolic activities of the cell. The efflux later served as a cue that reflects the activity of the cell that released the molecules. These cues can later evolve into paracrine signals. We further suggest that the signals used in paracrine signaling were adopted by the central nervous system, as peripheral cells were already attentive to these signals. Signaling molecules released by the target cells of neurons, as an inevitable consequence of the activities of the target cells, could function as retrograde signals of the activity of the target cell. We hypothesize that ACh released by innervated myocytes functions as a retrograde signal of myocyte response to neuronal stimulation.