Regulated Extracellular Nucleotide Metabolism and Function at the Mucosa

Abstract

Within mucosal tissues, regulation of nucleotide metabolism may be directed at various physiological/pathophysiological levels by myriad cell types. Adenosine (Ado) can regulate a number of processes at the mucosa, e.g. dampening of the inflammatory response and resultant tissue protection. Ado receptors are widely expressed on a variety of organs and cell types and have been demonstrated to be central to the modulation of inflammation. In many instances, local Ado levels are dictated by extracellular sources of adenine nucleotides. Activated neutrophils and platelet degranulation are two such important sources of ATP and ADP. Sequential phosphohydrolysis of adenine nucleotides by CD39 and CD73 results in the conversion of ATP and ADP to AMP, and the subsequent conversion of AMP to Ado, whereby signaling through Ado receptors can elicit effects such as increase in endothelial barrier function, increase in epithelial electrogenic Cl- secretion and water transport. Further regulation of Ado signaling has been observed under hypoxic conditions, due to hypoxia-inducible factor-1 (HIF-1)-regulated expression of A2BR and CD73, whereby additional SP-1 transcription factor activity has been identified as being required for hypoxic induction of CD39 expression in endothelial cells. Here we describe the different levels of regulation of adenine nucleotide metabolism and the resultant functional cell-cell signaling at the mucosa.