UIC - DDN - GALANIN-1 RECEPTOR

BENYA LAB - GALANIN-1 RECEPTOR:

Galanin is widely expressed in the central nervous system, and in the gastrointestinal (GI) tract by enteric nerves. This receptor is known to bind to specific receptors, Gal1R, Gal2R, and Gal3R. In in the GI tract, galanin receptors are expressed by smooth muscle cells which when activated modulate intestinal transit. We have shown that epithelial cells lining the human GI tract express only GalR1, and which when activated cause chloride secretion from these cells. We have shown that Gal1R expression is transcriptionally regulated by the inflammation-associated transcription factor NF-kappa B. NF-kappa B is activated in a number of inflammatory states including Crohns disease, ulcerative colitis, and infectious colitis, conditions that we have shown also show an increase in Gal1R expression. We therefore hypothesize that Gal1R expression and activation represents a common, unifying pathway accounting for the diarrhea associated with inflammatory conditions affecting the colon.

Basic Science: We cloned the human GAL1R gene and showed that it contains a number of unusual features for heptaspanning receptor genes including the absence of TATA boxes and a high GC content, typical of housekeeping genes. Yet we have shown that this gene is transcriptionally regulated, primarily by the inflammation-associated transcription factor NF-kB. All inflammatory events activating NF-kB including infection with enteric pathogens, Crohn's disease and ulcerative colitis result in increased GalR1 expression by epithelial cells lining the GI tract.

Clinical Science: Expression of the GalR1 receptor is altered in human colonocytes by exposure to various enteric pathogens of the GI tract, and in patients suffering from inflammatory disorders including Crohn's disease and ulcerative colitis. The functional consequence of this increased expression is increased Cl- secretion. Thus galanin and GalR1 may represent a common unifying pathway for the excessive fluid secretion, or diarrhea, observed in many inflammatory disorders of the colon.

Pathogenic Escherichia coli increase Cl- secretion from intestinal epithelial by up-regulating galanin-1 receptor expression. J Clin Invest 1999; 104: 253-262

Galanin-1 receptor up-regulation mediates the excess colonic fluid production caused by infection with enteric pathogens. Nature Med 2000; 6: 1048-1051.