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

J Neurosci. 2001 Aug 15;21(16):6348-61. doi: 10.1523/JNEUROSCI.21-16-06348.2001.

Abstract

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Constipation / physiopathology
  • Diarrhea / physiopathology
  • Dopamine Plasma Membrane Transport Proteins
  • Enteric Nervous System / cytology
  • Enteric Nervous System / metabolism
  • Epithelial Cells / metabolism
  • Ganglia / metabolism*
  • Gastrointestinal Motility / physiology
  • Heterozygote
  • Homozygote
  • In Vitro Techniques
  • Intestinal Mucosa / metabolism*
  • Mast Cells / metabolism
  • Membrane Glycoproteins / deficiency*
  • Membrane Glycoproteins / genetics
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Membrane Transport Proteins*
  • Mice
  • Mice, Knockout
  • Nerve Tissue Proteins*
  • Neurons / metabolism
  • Organ Specificity
  • Organic Cation Transport Proteins*
  • Organic Cation Transporter 1
  • Physical Stimulation
  • RNA, Messenger / metabolism
  • Serotonin / metabolism*
  • Serotonin / pharmacokinetics
  • Serotonin Plasma Membrane Transport Proteins

Substances

  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Organic Cation Transport Proteins
  • Organic Cation Transporter 1
  • RNA, Messenger
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a3 protein, mouse
  • Slc6a4 protein, mouse
  • solute carrier family 22 (organic cation transporter), member 3
  • Serotonin