## 3 Neurons and Neurochemistry of the Enteric Nervous System
Neurons expressing VIP are found in all four enteric neuron types. While NO modulates cGMP levels, VIP can activate the enzyme adenylate cyclase, thereby increasing cellular cAMP levels. In a subset of enteric neurons, VIP and NO act as co-transmitters in synergy to promote smooth muscle cell relaxation. Glutamate acts in concert with other neurotransmitters. It is co-expressed with acetylcholine, SP, in rodent enteric neurons and its stimulatory effects on NOS have also been described. Glutamic acid produced in the intrinsic motor neurons of the myenteric plexus acts on two types of ionotropic receptors: the normally fast-response \(\alpha\)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and the slowly activating \(N\)-methyl-D-aspartate (NMDA) receptors. Glutamate's special role is reflected in the fact that it was the first neurotransmitter to be detected in ascending intestinalofacial projections that reach up to the brain. The role of this neurotransmitter in the functioning of the gut-brain axis has since become unquestioned. Interestingly, one of the most common inhibitory neurotransmitters of the central nervous system, gamma-aminobutyrate (GABA), can depolarize postsynaptic cells in the alimentary canal. Smooth muscle contraction and relaxation can occur as a result of the GABAergic effect. GABAergic neurons appear to function as interneurons and can exert their effects on two types of receptors: excitatory GABAA\({}_{\text{A}}\) and inhibitory GAB\({}_{\text{B}}\) receptors. Through the GABA\({}_{\text{A}}\) receptor, it exerts a motility stimulating effect on excitatory cholinergic and noradrenergic enteric projections, while it generates smooth muscle relaxation by activating nitric neurons. There is more evidence that GABA is also expressed in neurons of the submucosal plexus and is secreted paracrinally in mucosal enteroendocrine cells, thereby affecting absorption, secretion, and the intestinal immune system [36; 37]. However, it is hard to build a universal classification of enteric neurons. Our conceptual understanding of enteric neurons and circuits comes from guinea pig studies: intrinsic afferent neurons, different types of ascending and descending interneurons, and muscle or mucosal motor neurons were identified in this species. Detailed knowledge on neuronal substances occurs from variety of gut segments from guinea pig, such as the small intestine [38; 39], the colon [40] and the stomach [41]. Regional differences in the connectivity of the enteric nervous system (ENS) were observed in mice between the proximal versus distal colon, as well [42]. Our knowledge of human enteric neuron classes [43; 44] and circuits [45] is much more limited due to the restricted access to human tissues. It is not possible to get a general picture--among other reasons--because of the differences between species. Furthermore, the 'one neuron--one function' concept is not supported anymore: intrinsic primary afferent neurons (IPANs) have been shown to be interneurons [46] and non-IPANs can also be regarded as sensory neurons [47; 48]. Under experimental and pathological conditions the chemical coding of neurons may change [44]. The difficulty of combining different groupings, the difficulty of resolving discrepancies and technological advances have given rise to recent groupings based on scRNA sequencing data [49; 50; 51; 52], which must be also integrated into the framework of ENS. The different cell types are shown in Figure 2 corresponding to their number.