Reduced expression of voltage-gated Kv11.1 (hERG) K(+) channels in aganglionic colon in Hirschsprung's disease.

Abstract

The pathophysiology of Hirschsprung's disease (HSCR) is not entirely understood. There is no clear explanation for the occurrence of the spastic or tonically contracted aganglionic segment of bowel. Kv11.1 (hERG) channels play a critical role in the regulation of the resting membrane potential as well as affecting either the force or frequency of contraction of smooth muscles. We designed this study to investigate the expression and distribution of hERG channels in the normal colon and the colon of patients with HSCR. We investigated hERG protein expression in both the ganglionic and aganglionic regions of HSCR patients (n=10) versus normal control colon (n=10). Protein distribution was assessed using immunofluorescence and confocal microscopy. Gene and protein expressions were quantified using real-time polymerase chain reaction, western blot analysis and densitometry. Confocal microscopy of the normal colon revealed strong hERG channel expression in interstitial cells of Cajal, platelet-derived growth factor-alpha receptor- (PDGFRα(+)) positive cells and enteric neurons. hERG expression was markedly decreased in aganglionic bowel, whereas colonic hERG gene expression levels were significantly decreased in aganglionic compared to ganglionic bowel and controls (p<0.05). Western blotting revealed decreased colonic hERG protein expression in aganglionic HSCR specimens compared to controls. We demonstrate, for the first time, the expression and distribution of hERG channels in the human colon. The decreased expression of hERG in the aganglionic colon may be responsible for the increased tone in the aganglionic narrow spastic segment of bowel.