Pre-neuronal acetylcholine: Non-neuronal cholinergic cells communicate to sensory neurons

Acetylcholine, the first identified neurotransmitter, is particularly abundant in the peripheral nervous system, being the primary neurotransmitter of α-motoneurons, all preganglionic autonomic and many, mostly parasympathetic, postganglionic autonomic neurons. Later on, it has been realized that many non-neuronal cells, in particular epithelial cells and cells of the immune system, also utilize acetylcholine as an autocrine and paracrine signalling molecule (“non-neuronal cholinergic system”), and is considered to be evolutionarily older than cholinergic neurotransmission. There is now increasing evidence that such non-neuronal acetylcholine takes influence upon the nervous system via cholinergic receptors on primary afferent neurons. Sensory neurons of murine dorsal root ganglia (DRG) express both muscarinic and nicotinic acetylcholine receptors (nAChR). Cholinergic receptors expressed by sensory neurons innervating the urinary bladder have received particular interest since they may be involved in the pathomechanisms underlying overactive bladder syndrome. As revealed by retrograde neuronal tracing experiments, 68% of bladder sensory neurons express the α3-nAChR subunit, in contrast to 7% and 6% of sensory neurons projecting to the foot skin and airways, respectively. According to their immunoreactivities for marker proteins, these cholinoceptive bladder sensory neurons belong to various functional classes, including myelinated mechanoreceptors and peptidergic and non-peptidergic nociceptors. Terminals of such sensory neurons penetrate the basal lamina to enter the bladder urothelium and the urethral epithelium. In the urethra, they make contact to a newly identified solitary, cholinergic, chemosensory cell which expresses the canonical taste transduction cascade, responds to bitter and umami tastants (which indicate bacterial colonization), and releases acetylcholine upon stimulation. Similar cells are also located at other mucosal surfaces and represent a sentinel system for potentially harmful substances initiating protective local reactions and classical reflexes via cholinergic signalling.