Nucleotides within the liquid film lining the epithelia of the airways control the mucociliary (MCC) clearanceprocess that removes inhaled noxious materials. ATP, UTP, UDP, and adenosine activate a subset ofpurinergic receptors that regulate ion secretion, increase ciliary beat frequency, and promote mucinsecretion. In addition, UTP, ATP, and UDP-glucose are potent neutrophil chemoattractants, suggesting thatnucleotides released onto airway surfaces may induce neutrophil migration in response to airway stress.Therefore, understanding the mechanism(s) of nucleotide release by airway epithelia has importantpathophysiological and therapeutic implications for the lung. Circumstantial evidence exists for two modes ofATP release from epithelial cells onto the airway surface: (i) ion channels and/or transporters and (ii)vesicles. However, whether nucleotides are released from the cytosol, from vesicles, or both compartmentsis not unambiguously known. Recognition that airway epithelial cells release UDP-sugars, donor substratesof glycosylation reactions in the endoplasmic reticulum and Golgi lumen, in addition to ATP, suggests thatnucleotides entering these organelles may be released by exocytosis. Preliminary data illustrating thatenhanced mucin secretion by cultured goblet-like cells is accompanied by release of UDP-glucose and ATPsuggest that nucleotide release by goblet cells reflects an exocytotic process associated with mucinsecretion. Preliminary data also suggests that NMP antiporters mediate the release of cytosolic UDP-sugarsin non-goblet cells. This application outlines a plan to define the role of vesicle and mucin granule exocytosisand of antiporter mechanisms in the release of nucleotides by airway epithelia. To accomplish this goal, wepropose the following Specific Aims: (1) to test the hypothesis that NTP/NDP release is vesicular, (2) to testthe hypothesis that nucleotide/NMP antiporters facilitate nucleotide release, and (3) to delineate therelationship between nucleotide release and mucin secretion. We will assess the extent to which nucleotiderelease reflects vesicle exocytosis, is modified by Golgi nucleotidases, involves Golgi and/or cell surfacetranslocators, and is mechanistically associated with mucin secretion. Completion of these studies willestablish mechanism(s) for the physiologically important process of nucleotide release, and accordingly willdelineate potential drug targets for airway diseases associated with poor MCC clearance.
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