Beate Illek, Horst Fischer, and Terry Machen (1998). Genetic disorders of membrane transport. II. Regulation of CFTR by small molecules including HCO-3. Am J Physiology. 275, G1221-G1226.       Cystic fibrosis (CF) affects a number of epithelial tissues, including those in the gastrointestinal tract. The goal of this review is to summarize data related to regulation of the protein product of the CF gene, CF transmembrane conductance regulator (CFTR), by a variety of small molecules. There has been a surge of interest in discovering small molecules that could be exogenously added to cells and tissues to regulate CFTR and could potentially be used alone or in combination with genetic approaches for therapy in CF. We will discuss the apparent mechanisms of action of genistein, milrinone, 8-cyclopentyl-1,3-dipropylxanthine, IBMX, and NS-004; several of which appear to interact directly with one or both nucleotide binding domains of CFTR. We also discuss how HCO3 interacts with CFTR as both a permeating anion and a potential regulator of Cl permeation through the CFTR ion channel. It is likely that there are complicated interactions between Cl and HCO3 in the secretion of both ions through the CFTR and the anion exchanger in intestinal cells, and these may yield a role of CFTR in regulation of intestinal HCO3 secretion as well as of intra- and extracellular pH.