Pathophysiology of Potassium (K+) Channels in Intestinal Disease
The group was the first to identify and characterise K+ channels in human colonic epithelial cells (Lancet 343, 23-25, 1994; Gut 38, 243-247, 1996). As part of an on-going programme of research into the molecular physiology of ion channels in human epithelia, current work is directed at the altered expression/activity of colonic K+ channels and their clinical relevance in ulcerative colitis (UC), end-stage renal disease (ESRD), malignant transformation of the colonic epithelium, and intestinal ischaemia during complex liver surgery. We have shown that high conductance (200pS) apical K+ (BK) channels are expressed along the entire surface cell-crypt cell axis in active and quiescent UC, in contrast to normal colon. This change may account for the increased faecal K+ losses often found in UC, and may also be related to the premalignant nature of UC since a variety of other K+ channels are known to be overexpressed in and linked to the growth of several cancer cells lines; epithelial cell cancers, gliomas and melanomas. We are presently evaluating K+ expression at RNA and protein levels in human colonic polyps and cancers. We have also shown that increased expression of apical BK channels along the surface cell-crypt cell axis accounts for the increased colonic luminal K+ conductance that mediates increased colonic K+ secretion in patients with ESRD, thus enabling the colon to transform into a major accessory K+ excretory organ in this disease. Novel work over the past 2 years has shown rapid increases in colonic paracellular permeability during cell hypoxia which are dependent on basolateral IKCa channel activation.
Figure 1. Immunolocalisation of apical BK channel protein in normal sigmoid colon, ±-subunit antibody restricted to surface cells (A); sigmoid colon in mild UC, with crypt distortion, goblet cell depletion, microabscess formation(„), and localisation of ±-subunit antibody along the entire crypt (B); sigmoid colon in quiescent UC, with restoration of goblet cells and persistent localisation of BK channel ±-subunit antibody along the crypt axis (C). Haematoxylin counterstain.
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