Figure 10. Model of adenyl nucleotide regulation in ASL.

The schematic diagram represents a ciliated and a goblet cell of the airway surface epithelium. Mucin exocytosis from goblet cells is accompanied by release of adenyl nucleotides present in mucin granules as co-cargo molecules. ADP is the prevalent species followed by AMP and ATP. In ASL, ADP and AMP (and ATP) are rapidly metabolized by ecto-nucleotidases into adenosine. Adenyl purines have autocrine and paracrine regulatory activities on epithelial cells. For example, adenosine stimulates the A_2b receptor on ciliated cells. CFTR, which is expressed in ciliated cells, is activated by A_2b receptor-promoted cAMP formation (and PKA activation, not shown). Thus, chloride secretion is increased and sodium absorption is reduced (by CFTR-mediated inhibition of ENaC), which generates the driving gradient for water secretion necessary to disperse newly secreted mucins into the ASL. ATP released from mucin granules stimulates P2Y₂ receptors on goblet cells for further mucin secretion, and on ciliated cells resulting in activation of TMEM16A or CACC (calcium activated chloride channel), activation of CFTR (via PKC), and inhibition of ENaC.