Regulation of the CFTR channel by phosphorylation

Cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel s are regulated tightly by protein kinases and phosphatases. The regulatory domain of CFTR has about 20 potential sites for phosphorylation by protein kinases A (PKA) and C (PKC). The reason for this large number of sites is not known, however their conservation from fish to humans implies that they play important roles in vivo. PKA is an important activator, and its stimu lation of CFTR is enhanced by PKC via mechanisms which are not fully unders tood. The physiological stimuli of CFTR are not known for some epithelia, a nd it appears likely that other serine/threonine and even tyrosine kinases also regulate CFTR in particular tissues. Phosphatases that deactivate CFTR have yet to be identified definitively at the molecular level, however CFT R is regulated by a membrane-bound form of protein phosphatase-2C (PP2C) in several cell types. Patch-clamp studies of channel rundown, coimmunoprecip itation, chemical cross-linking studies, and pull-down assays all indicate that CFTR and PP2C are closely associated within a stable regulatory comple x. Understanding the regulation of CFTR by PP2C is a priority due to its po tential as a target for pharmacotherapies in the treatment of cystic fibros is.