Differential activation of the HCO3‐ conductance through the cystic fibrosis transmembrane conductance regulator anion channel by genistein and forskolin in murine duodenum

• Published in: British journal of pharmacology 2009-11, Vol.158 (5), p.1313-1321
• Main Authors: Tuo, Biguang, Wen, Guorong, Seidler, Ursula
• Format: Article
• Language: English
• Subjects: bicarbonate secretion; Biological and medical sciences; CFTR; duodenum; Errors of metabolism; Medical sciences; Metabolic diseases; Miscellaneous hereditary metabolic disorders; Pharmacology. Drug treatments; Research Papers
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2009.00398.x

Background and purpose:  Many cystic fibrosis (CF)‐associated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels affect CFTR‐activated HCO3‐ transport more than Cl‐ transport. Targeting the CFTR HCO3‐ conductance, if possible, may therefore be of major therapeutic benefit. In the present study, we examined the effects of genistein and forskolin on duodenal mucosal HCO3‐ and Cl‐ secretion. Experimental approach:  Murine duodenal mucosal HCO3‐ and Cl‐ secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (Isc) techniques. Key results:  Genistein markedly stimulated duodenal HCO3‐ secretion and Isc in a dose‐dependent manner in CFTR wild‐type mice, but not in CFTR null mice. CFTRinh‐172, a highly specific CFTR inhibitor, inhibited genistein‐stimulated duodenal HCO3‐ secretion and Isc in wild‐type mice. Genistein induced 59% net HCO3‐ increase and 123% net Isc increase over basal value, whereas forskolin, an activator of adenylate cyclase, induced 94% net HCO3‐ increase and 507% net Isc increase, indicating that, compared with forskolin, genistein induced a relatively high HCO3‐/Isc ratio. Further data showed that CFTR HCO3‐/Cl‐ conductance ratio was 1.05 after genistein stimulation, whereas after forskolin stimulation, the CFTR HCO3‐/Cl‐ conductance ratio was 0.27. Conclusions and implications:  Genistein stimulates duodenal HCO3‐ and Cl‐ secretion through CFTR, and has a relatively high selectivity for the CFTR HCO3‐ conductance, compared with forskolin. This may indicate the feasibility of selective targeting of the HCO3‐ conductance of the CFTR channels.