Maintenance of serotonin in the intestinal mucosa and ganglia of mice that lack the high-affinity serotonin transporter: Abnormal intestinal motility and the expression of cation transporters.
The enteric serotonin reuptake transporter (SERT) has been proposed to play a critical role in serotonergic neurotransmission and in the initiation of peristaltic and secretory reflexes. We analyzed potential compensatory mechanisms and enteric function in the bowels of mice with a targeted deletion of SERT. The guts of these animals were found to lack mRNA encoding SERT; moreover, high-affinity uptake of 5-HT into epithelial cells, mast cells, and enteric neurons was present in the SERT +/+ bowel but absent in the SERT -/- bowel. However, both the SERT +/+ gut and the -/- gut expressed molecules capable of transporting 5-HT, but with affinities and selectivity much lower than those of SERT. These included the dopamine transporter (DAT) and polyspecific organic cation transporters OCT-1 and OCT-3. DAT and OCT immunoreactivities were present in both the submucosal and myenteric plexuses, and the OCTs were also located in the mucosal epithelium. 5-HT was found in all of its normal sites in the SERT -/- bowel, which contained mRNA encoding tryptophan hydroxylase, but no 5-HT was present in the blood of SERT -/- animals. Stool water and colon motility were increased in most SERT -/- animals; however, the increase in motility (diarrhea) occasionally alternated irregularly with decreased motility (constipation). The watery diarrhea is probably attributable to the potentiation of serotonergic signaling in SERT -/- mice, whereas the transient constipation may be caused by episodes of enhanced 5-HT release leading to 5-HT receptor desensitization.
Chen
J J
JJ
Department of Anatomy and Cell Biology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Li
Z
Z
Pan
H
H
Murphy
D L
DL
Tamir
H
H
Koepsell
H
H
Gershon
M D
MD
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D003248:Constipation / Q000503:physiopathology; D003967:Diarrhea / Q000503:physiopathology; D050483:Dopamine Plasma Membrane Transport Proteins; D017615:Enteric Nervous System / Q000166:cytology / Q000378:metabolism; D004847:Epithelial Cells / Q000378:metabolism; D005724:Ganglia / Q000378:metabolism*; D005769:Gastrointestinal Motility / Q000502:physiology; D006579:Heterozygote; D006720:Homozygote; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D008407:Mast Cells / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000378:metabolism; D009928:Organ Specificity; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D010812:Physical Stimulation; D012333:RNA, Messenger / Q000378:metabolism; D012701:Serotonin / Q000378:metabolism* / Q000493:pharmacokinetics; D050486:Serotonin Plasma Membrane Transport Proteins; D000099254:Organic Cation Transporter 3
D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D027701:Organic Cation Transport Proteins; D027702:Organic Cation Transporter 1; D012333:RNA, Messenger; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D000099254:Organic Cation Transporter 3; C493215:Slc6a3 protein, mouse; C493231:Slc6a4 protein, mouse