. 5-HT2A receptors: location and functional analysis in intestines of wild-type and 5-HT2A knockout mice. Am J Physiol Gastrointest Liver Physiol 282: G877-G893, 2002. First published January 9, 2002 10.1152/ajpgi.00435.2001.-The distribution and function of the 5-hydroxytryptamine (5-HT2A) receptor were investigated in the intestines of wild-type (5-HT2A ϩ/ϩ) and knockout (5-HT2A Ϫ/Ϫ) mice. In 5-HT2A ϩ/ϩ mice, rats, and guinea pigs, 5-HT2A receptor immunoreactivity was found on circular and longitudinal smooth muscle cells, neurons, enterocytes, and Paneth cells. Muscular 5-HT2A receptors were concentrated in caveolae; neuronal 5-HT2A receptors were found intracellularly and on the plasma membranes of nerve cell bodies and axons. Neuronal 5-HT2A immunoreactivity was detected as early as E14 in ganglia, intravillus nerves, and the deep muscle plexus. The 5-HT2A Ϫ/Ϫ colon did not express 5-HT2A receptors and did not contract in response to exogenous 5-HT. 5-HT2A Ϫ/Ϫ enterocytes were smaller, Paneth cells fewer, and muscle layers thinner (and showed degeneration) compared with those of 5-HT2A ϩ/ϩ littermates. The 5-HT2A receptor may thus be required for the maintenance and/or development of enteric neuroeffectors and other enteric functions, although gastrointestinal and colonic transit times in 5-HT2A Ϫ/Ϫ and ϩ/ϩ mice did not differ significantly. serotonin receptors; intestinal motility; immunocytochemistry THE ENTERIC NERVOUS SYSTEM (ENS) is different from the autonomic innervation of other organs, because it can mediate coordinated behaviors of the gut without central nervous system input (28,32,53). The presence in the bowel of intrinsic primary afferent neurons (IPANs) enables the ENS to respond to luminal stimuli. Because no nerve fibers enter the lumen, Bü lbring and Crema (7) proposed that sensory transduction is transepithelial, involving the pressure-induced secretion of 5-HT from enterochromaffin (EC) cells to stimulate the mucosal processes of the submucosal IPANs that initiate reflexes. This hypothesis has since been confirmed, and EC cell-derived 5-HT is now thought to activate both peristaltic (21,36,37,47,50,63) and secretory reflexes (12,73).In addition to its role in the initiation of enteric reflexes, 5-hydroxytryptamine (5-HT) also functions in ganglionic neurotransmission within the ENS. A subset of myenteric interneurons is serotonergic (8,13,22,29,31,76,77); therefore, 5-HT antagonists can block peristaltic reflexes by inhibiting enteric serotonergic neurotransmission (46, 60, 82) as well as by interfering with the paracrine stimulation of IPANs. 5-HT from EC cells also plays a role in extrinsic sensation by stimulating extrinsic primary afferent nerves (2, 39, 40).The bowel contains an abundance of 5-HT receptor subtypes located on neurons, smooth muscle, and epithelial cells (24,25,30). Enteric neuronal 5-HT receptors include 5-HT 1A (26,48,49,62), 5-HT 1P (6, 59, 64), 5-HT 2B (18), 5-HT 3 (15,25,42,59), and 5-HT 4 (36,37,62,80). Enteric members of the 5-HT 2 family are associated with s...