Chloride secretion in response to guanylin in colonic epithelial from normal and transgenic cystic fibrosis mice.
1. Guanylin, a 15 amino acid endogenous gut peptide, increased the short circuit current (SCC) in the epithelium of the mouse colon, but only when applied to the apical and not the basolateral surface. 2. By use of selective blockers of epithelial ion transport and modification of the bathing solution, it was concluded that guanylin increased electrogenic chloride secretion but also had a minor effect on electrogenic sodium absorption. In addition there were small residual currents which remained unresolved. 3. The threshold concentration of guanylin causing a SCC increase was less than 50 nM, but at concentrations 40 times greater no indication of a maximally effective concentration was found. 4. Two guanylin isomers with the same amino acid sequence but with the disulphide bridges joined in an alternate fashion showed no activity. Thus only guanylin with the greatest structural homology to heat stable enterotoxin (STa) showed biological activity. 5. The action of guanylin was virtually eliminated in colonic epithelia from transgenic cystic fibrosis (CF) mice. As these animals lack the chloride channel coded by the CF gene sequence, it is likely that the final effector process in murine colonic epithelia involves the CFTR (cystic fibrosis transmembrane conductance regulator) chloride channel. 6. Opportunistic infections of the gut generating STa lead to diarrhoeal conditions via an action of the toxin on apical guanylin receptors. Thus, as discussed, the CF heterozygote may have a genetic advantage in this circumstance.
Cuthbert
A W
AW
Department of Pharmacology, Glaxo Institute of Applied Pharmacology, Cambridge.
Hickman
M E
ME
MacVinish
L J
LJ
Evans
M J
MJ
Colledge
W H
WH
Ratcliff
R
R
Seale
P W
PW
Humphrey
P P
PP
D000595:Amino Acid Sequence; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D018118:Chloride Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002712:Chlorides / Q000378:metabolism*; D003106:Colon / Q000187:drug effects / Q000378:metabolism; D003550:Cystic Fibrosis / Q000235:genetics / Q000378:metabolism*; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D004768:Enterotoxins / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D006579:Heterozygote; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007536:Isomerism; D008565:Membrane Proteins / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D045265:Natriuretic Peptides; D010455:Peptides / Q000494:pharmacology*
D001427:Bacterial Toxins; D018118:Chloride Channels; D002712:Chlorides; D004768:Enterotoxins; D029968:Escherichia coli Proteins; D005768:Gastrointestinal Hormones; D008565:Membrane Proteins; D045265:Natriuretic Peptides; D010455:Peptides; C034151:heat stable toxin (E coli); D019005:Cystic Fibrosis Transmembrane Conductance Regulator; C072685:guanylin