Figure 1.

Model of purinergic signaling in airway epithelia. Mechanical stimulation of the epithelial surface by mechanical stress, irritants, or pathogens induces ATP release and elevates ASL (ATP). ATP is an agonist to a series of purinoceptors, including the G-protein-coupled P2Y₂ receptor located on the luminal surface of the airway lumen. Upon P2Y₂ receptor activation, the rate of PIP₂ hydrolysis increases, resulting in an increase in IP₃ and release of Ca²⁺ from stores. Increased levels of intracellular Ca²⁺ are responsible for activating CaCC (TMEM16a), resulting in a stimulation in Cl⁻ secretion. Additionally, the reduction in PIP2 also results in a decrease in ENaC-mediated sodium absorption. The action of a series of ectonucleotidases converts the extracellular ATP to ADP, AMP, and eventually adenosine (ADO). Adenosine is a potent agonist of adenosine receptors, such as the A_2b receptor, expressed on the airway surface. Activation of these receptors induces G-protein-coupled adenylate cyclase, followed by cAMP-dependent activation of protein kinase A. The result is stimulation of CFTR-mediated Cl⁻ secretion. In addition to modulation of ion channel activity, stimulation of ATP release is a well-known agonist for stimulating mucin release (via P2Y₂ receptor activation) and cilia beat frequency (via both P2Y₂ and A_2b). Together, the action of mechanical stress is the stimulation of fluid secretion and acceleration of mucus transport rates.