Intestinal ion transport in NKCC1-deficient mice.
The Na(+)-K(+)-2Cl(-) cotransporter (NKCC1) located on the basolateral membrane of intestinal epithelia has been postulated to be the major basolateral Cl(-) entry pathway. With targeted mutagenesis, mice deficient in the NKCC1 protein were generated. The basal short-circuit current did not differ between normal and NKCC1 -/- jejuna. In the -/- jejuna, the forskolin response (22 microA/cm(2); bumetanide insensitive) was significantly attenuated compared with the bumetanide-sensitive response (52 microA/cm(2)) in normal tissue. Ion-replacement studies demonstrated that the forskolin response in the NKCC1 -/- jejuna was HCO(3)(-) dependent, whereas in the normal jejuna it was independent of the HCO(3)(-) concentration in the buffer. NKCC1 -/- ceca exhibited a forskolin response that did not differ significantly from that of normal ceca, but unlike that of normal ceca, was bumetanide insensitive. Ion-substitution studies suggested that basolateral HCO(3)(-) as well as Cl(-) entry (via non-NKCC1) paths played a role in the NKCC1 -/- secretory response. In contrast to cystic fibrosis mice, which lack both basal and stimulated Cl(-) secretion and exhibit severe intestinal pathology, the absence of intestinal pathology in NKCC1 -/- mice likely reflects the ability of the intestine to secrete HCO(3)(-) and Cl(-) by basolateral entry mechanisms independent of NKCC1.
Grubb
B R
BR
Cystic Fibrosis/Pulmonary Research and Treatment Center, University of North Carolina, Chapel Hill, North Carolina 27599-7248, USA. bgrubb@med.unc.edu
Lee
E
E
Pace
A J
AJ
Koller
B H
BH
Boucher
R C
RC
D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid / Q000494:pharmacology; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D002034:Bumetanide / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D002432:Cecum / Q000187:drug effects / Q000502:physiology*; D002712:Chlorides / Q000378:metabolism*; D005576:Colforsin / Q000494:pharmacology; D005947:Glucose / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000187:drug effects / Q000502:physiology*; D007583:Jejunum / Q000187:drug effects / Q000502:physiology*; D007700:Kinetics; D008565:Membrane Proteins / Q000172:deficiency / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D016296:Mutagenesis; D011188:Potassium / Q000378:metabolism*; D012964:Sodium / Q000378:metabolism*; D028021:Sodium-Potassium-Chloride Symporters
D001639:Bicarbonates; D002352:Carrier Proteins; D002712:Chlorides; D008565:Membrane Proteins; D028021:Sodium-Potassium-Chloride Symporters; D002034:Bumetanide; D005576:Colforsin; D012964:Sodium; D005947:Glucose; D017878:4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid; D011188:Potassium