Disruption of the K+ channel beta-subunit KCNE3 reveals an important role in intestinal and tracheal Cl- transport.
The KCNE3 beta-subunit constitutively opens outwardly rectifying KCNQ1 (Kv7.1) K(+) channels by abolishing their voltage-dependent gating. The resulting KCNQ1/KCNE3 heteromers display enhanced sensitivity to K(+) channel inhibitors like chromanol 293B. KCNE3 was also suggested to modify biophysical properties of several other K(+) channels, and a mutation in KCNE3 was proposed to underlie forms of human periodic paralysis. To investigate physiological roles of KCNE3, we now disrupted its gene in mice. kcne3(-/-) mice were viable and fertile and displayed neither periodic paralysis nor other obvious skeletal muscle abnormalities. KCNQ1/KCNE3 heteromers are present in basolateral membranes of intestinal and tracheal epithelial cells where they might facilitate transepithelial Cl(-) secretion through basolateral recycling of K(+) ions and by increasing the electrochemical driving force for apical Cl(-) exit. Indeed, cAMP-stimulated electrogenic Cl(-) secretion across tracheal and intestinal epithelia was drastically reduced in kcne3(-/-) mice. Because the abundance and subcellular localization of KCNQ1 was unchanged in kcne3(-/-) mice, the modification of biophysical properties of KCNQ1 by KCNE3 is essential for its role in intestinal and tracheal transport. Further, these results suggest KCNE3 as a potential modifier gene in cystic fibrosis.
Preston
Patricia
P
Leibniz-Institut für Molekulare Pharmakologie and Max-Delbrück-Centrum für Molekulare Medizin, 13125 Berlin, Germany.
Wartosch
Lena
L
Günzel
Dorothee
D
Fromm
Michael
M
Kongsuphol
Patthara
P
Ousingsawat
Jiraporn
J
Kunzelmann
Karl
K
Barhanin
Jacques
J
Warth
Richard
R
Jentsch
Thomas J
TJ
D000818:Animals; D002460:Cell Line; D002712:Chlorides / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D051657:KCNQ1 Potassium Channel / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D018408:Patch-Clamp Techniques; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D045442:Rotarod Performance Test; D013270:Stomach / Q000166:cytology; D014018:Tissue Distribution; D014132:Trachea / Q000166:cytology / Q000378:metabolism*
D002712:Chlorides; D051657:KCNQ1 Potassium Channel; C498827:Kcne3 protein, mouse; D024642:Potassium Channels, Voltage-Gated; D021122:Protein Subunits