Purinergic receptors in airway epithelia

Abstract

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.

Figure 1. Pathways for ATP release

Several scenarios possibly account for the basal and stimulated release of nucleotides from airway epithelial cells. (i) ATP entering the Golgi lumen via specific transporters may be released as a residual cargo product of the constitutive secretory pathway. (ii) Secretory granules (e.g., mucin granules) containing ATP may be competent for Ca²⁺-regulated exocytosis. (iii) A not yet identified ATP conductance effluxes cytosolic ATP out of the cells.

Figure 2. Purinergic regulation of ion transport

ASL ATP promotes P2Y₂ receptor-mediated Ca²⁺-activated Cl^- channel (CaCC) activity, and inhibition of the epithelial Na⁺ channel ENaC (via PIP₂ depletion, not shown). Potentially, the P2Y₂ receptor promotes PKC-mediated CFTR activation. ATP hydrolysis results in adenosine accumulation (ADO), which in turns activates the A_2b receptor, leading to cyclic AMP (cAMP) and protein kinase A (PKA)-mediated CFTR activation. CFTR inhibits ENaC by mechanisms that are not well understood.