Polarized signaling via purinoceptors in normal and cystic fibrosis airwayepithelia

Airway epithelia are confronted with distinct signals emanating from the lu minal and/or serosal environments. This study tested whether airway epithel ia exhibit polarized intracellular free calcium (Ca-i(2+)) and anion secret ory responses to 5' triphosphate nucleotides (ATP/UTP), which may be releas ed across both barriers of these epithelia. In both normal and cystic fibro sis (CF) airway epithelia, mucosal exposure to ATP/UTP increased Ca-i(2+) a nd anion secretion, but both responses were greater in magnitude for CF epi thelia. In CF epithelia, the mucosal nucleotide-induced response was mediat ed exclusively via Ca-i(2+) interacting with a Ca2+-activated Cl- channel ( CaCC). In normal airway epithelia (but not CF), nucleotides stimulated a co mponent of anion secretion via a chelerythrine-sensitive, Ca2+-independent PKC activation of cystic fibrosis transmembrane conductance regulator. In n ormal and CF airway epithelia, serosally applied ATP or UTP were equally ef fective in mobilizing Ca-i(2+). However, serosally applied nucleotides fail ed to induce anion transport in CF epithelia, whereas a PKC-regulated anion secretory response was detected in normal airway epithelia. We conclude th at (1) in normal nasal epithelium, apical/basolateral purinergic receptor a ctivation by ATP/UTP regulates separate Ca2+-sensitive and Ca2+-insensitive (PKC-mediated) anion conductances; (2) in CF airway epithelia, the mucosal ATP/UTP-dependent anion secretory response is mediated exclusively via Ca- i(2+); and (3) Ca-i(2+) regulation of the Ca2+-sensitive anion conductance (via CaCC) is compartmentalized in both CF and normal airway epithelia, wit h basolaterally released Ca-i(2+) failing to activate CaCC in both epitheli a.