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Nucleotides and nucleosides within the airway surface liquid regulate mucociliary clearance (MCC) activities, the primary innate defense mechanism that removes foreign particles and pathogens from airway surfaces. Nucleotide and nucleoside actions in the airways are mediated mainly by two purinergic receptor subtypes, the Gq-coupled ATP/UTP-sensing P2Y2 receptor and the Gs-coupled A2b adenosine receptor. Activation of the A2b receptor results in cyclic AMP-dependent activation of the cystic fibrosis transmembrane regulator (CFTR) Cl− channel and stimulation of ciliary beat frequency. Agonist occupation of the P2Y2 receptor promotes inhibition of Na+ absorption as well as CFTR-dependent and CFTR-independent Cl− secretion, ciliary beating, and mucin secretion.