Potential role of reduced basolateral potassium (IKCa3.1) channel expression in the pathogenesis of diarrhoea in ulcerative colitis.
Diarrhoea in ulcerative colitis (UC) mainly reflects impaired colonic Na(+) and water absorption. Colonocyte membrane potential, an important determinant of electrogenic Na(+) absorption, is reduced in UC. Colonocyte potential is principally determined by basolateral IK (KCa3.1) channel activity. To determine whether reduced Na(+) absorption in UC might be associated with decreased IK channel expression and activity, we used molecular and patch clamp recording techniques to evaluate IK channels in colon from control patients and patients with active UC. In control patients, immunolabelling revealed basolateral IK channels distributed uniformly along the surface-crypt axis, with substantially decreased immunolabelling in patients with active UC, although IK mRNA levels measured by quantitative PCR were similar in both groups. Patch clamp analysis indicated that cell conductance was dominated by basolateral IK channels in control patients, but channel abundance and overall activity were reduced by 53% (p = 0.03) and 61% (p = 0.04), respectively, in patients with active UC. These changes resulted in a 75% (p = 0.003) decrease in the estimated basolateral membrane K(+) conductance in UC patients compared with controls. Levels of IK channel immunolabelling and activity in UC patients in clinical remission were similar to those in control patients. We conclude that a substantial decrease in basolateral IK channel expression and activity in active UC most likely explains the epithelial cell depolarization observed in this disease, and decreases the electrical driving force for electrogenic Na(+) transport, thereby impairing Na(+) absorption (and as a consequence, Cl(-) and water absorption) across the inflamed mucosa.
Institute of Membrane and Systems Biology, University of Leeds, UK.
Adel
A
Al-Hazza
John E
JE
Linley
Qadeer
Q
Aziz
Kenneth A
KA
Maclennan
Malcolm
M
Hunter
Geoffrey I
GI
Sandle
D003093:Colitis, Ulcerative / Q000150:complications* / Q000378:metabolism; D003967:Diarrhea / Q000209:etiology* / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology; D006801:Humans; D007150:Immunohistochemistry; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D018408:Patch-Clamp Techniques; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism
D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; C496923:KCNN4 protein, human; D012333:RNA, Messenger