Novel mechanisms of neuronal and hormonal regulation of large intestinal electrolyte transport

The mammalian colon plays a vital role in maintaining overall electrolyte and fluid homeostasis in the body, and it possesses the ability to either secrete or absorb water depending upon the needs of the organism. Secretion or absorption of electrolyte ions, such as Na+, Cl- and K+, drives the movement of water across the colonic epithelium – the inner gut lining where all transport takes place. Aberrant absorptive and/or secretory activity within the colonic epithelium is central to the pathogenesis of many gastrointestinal diseases, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), constipation and infectious diarrhea. As such, therapeutic control of colonic electrolyte transport is critical to the management of these conditions. Two of its most important regulators – the enteric nervous system (ENS) and the corticosteroid hormones – provide key avenues by which colonic epithelial transport activity can be modulated or corrected, in the case of pharmacotherapeutic intervention. The work described in this dissertation characterizes two separate, novel aspects of regulatory control that may be the targets of future therapeutic drug development. First is the discovery and characterization of voltage gated K+ (KV7) channels in the ENS as governors of ENS activity and resultant epithelial transport function. Second is the study of the epithelial N+, K+, 2Cl- (NKCC1) co-transporter and its regulation by the corticosteroid hormone, aldosterone, in controlling epithelial K+ and Cl- transport. The findings from this work set the stage for development of targeted therapies aimed at these two mechanisms, which may lead to improved management of intestinal pathologies such as IBS, IBD or other diarrheal conditions