Extracellular ATP: Important Developments in Purinergic Signaling

Adenosine 5’-triphosphate (ATP) is a nucleoside triphosphate composed of adenine, ribose, and three phosphate groups and is the principal carrier of chemical energy within the cell. Roughly 10 molecules of ATP are in solution throughout the intracellular space in a typical cell, providing energy for a large variety of biologic reactions that are energetically unfavorable and would otherwise not occur [4]. ATP also serves as the substrate for one of the most widely used intracellular signaling molecules, adenosine 3’,5’-cyclic monophosphate (cAMP), and is ubiquitous as a mediator of protein signaling through regulatory phosphorylation. While it has long been recognized that ATP serves as the substrate for one of the most common intracellular signaling molecules, it is more recently becoming apparent that ATP and other nucleotides also serve as potent extracellular signaling molecules. In fact, autocrine release of extracellular ATP is a ubiquitous biologic and physiologic process in numerous cell types including epithelial cells, endothelial cells, smooth muscle cells, fibroblasts, circulating lymphocytes, monocytes, red blood cells, mast cells, chondrocytes, excitatory neurons, platelets, hepatocytes, pancreatic β-cells and cholangiocytes [34]. ATP and other nucleotides exert potent autocrine and paracrine effects on cellular function through activation of purinergic receptors [12, 53]. In hepatocytes and cholangiocytes, activation of purinergic receptors through agonist binding has been linked to numerous fundamental biologic processes including cell volume regulation, glucose metabolism, bile formation, secretion and ion channel activation [40, 49, 50, 54]. Despite the recent advances in knowledge of extracellular signaling through purinergic receptors, the mechanisms of cellular ATP release remain unknown. It should be recognized that while this review focuses primarily on ATP, the mechanisms for nucleotide release presented apply to uridine nucleotides and nucleotide sugars, suggesting that these nucleotides are also capable of acting as autocrine/paracrine signaling molecules [10]. Historically, two broad models of nucleotide release have been recognized: exocytotic release of nucleotides involving the mobilization of vesicles rich in ATP, and channel-mediated release of ATP through various candidate transporters and/or exchangers. The mechanisms employed by a cell for nucleotide release will depend on the specific cell model studied and its purinergic receptor distribution. Accordingly this chapter will focus on the two principal epithelial cell types that are involved in most liver diseases: hepatocytes, which constitute the liver parenchyma, and cholangiocytes, which line the lumen of the bile ducts. The emerging role of extracellular nucleotides in the regulation of cellular physiology in these cell types was reviewed by Roman et al. [47]. This chapter builds on that work by following a similar format while focusing on more recent developments in the field.