Extracellular zinc and ATP-gated P2X receptor calcium entry channels: New zinc receptors as physiological sensors and therapeutic targets

In this review, we focus on two attributes of P2X receptor channel function, one essential and one novel. First, we propose that P2X receptors are extracellular sensors as well as receptors and ion channels. In particular, the large extracellular domain (that comprises 70% of the molecular mass of the receptor channel protein) lends itself to be a cellular sensor. Moreover, its exquisite sensitivity to extracellular pH, ionic strength, and multiple ligands evokes the function of a sensor. Second, we propose that P2X receptors are extracellular zinc receptors as well as receptors for nucleotides. We provide novel data in multiple publications and illustrative data in this invited review to suggest that zinc triggers ATP-independent activation of P2X receptor channel function. In this light, P2X receptors are the cellular site of integration between autocrine and paracrine zinc signaling and autocrine and paracrine purinergic signaling. P2X receptors may sense changes in these ligands as well as in extracellular pH and ionic strength and transduce these sensations via calcium and/or sodium entry and changes in membrane potential

Possible therapeutic benefits of zinc-based fourmations for cystic fibrosis

<p><b>Copyright information:</b></p><p>Taken from "Extracellular zinc and ATP-gated P2X receptor calcium entry channels: New zinc receptors as physiological sensors and therapeutic targets"</p><p></p><p>Purinergic Signalling 2005;1(4):299-310.</p><p>Published online Jan 2005</p><p>PMCID:PMC2096558.</p><p></p> Possible benefits of zinc are listed. Multiple CF defects could benefit by zinc binding to P2X receptor channels on or from zinc entry into CF human airway epithelial cells (see Figure for postulated benefits of zinc entry). An increase in Ca induced by zinc at P2X receptor or possible direct zinc inhibition would disable hyperactive ENaC channels. The sustained Ca entry signal mediated by P2X receptor channels would require KCl secretion and augment ciliary beat. The latter is not affected in CF; however, augmentation of ciliary beat can only help clear tenacious and dehydrated mucus

Cellular mechanisms of zinc's anti-inflammatory effects in epithelial cells and other cells? Zinc interactions with membrane receptors may have anti-inflammatory benefits

<p><b>Copyright information:</b></p><p>Taken from "Extracellular zinc and ATP-gated P2X receptor calcium entry channels: New zinc receptors as physiological sensors and therapeutic targets"</p><p></p><p>Purinergic Signalling 2005;1(4):299-310.</p><p>Published online Jan 2005</p><p>PMCID:PMC2096558.</p><p></p> However, if zinc could gain entry into airway epithelia, it is then free to bind to any and all enzymes that require it as a co-factor. Many effectors within inflammatory signaling cascades have zinc finger motifs. If zinc binding has a net inhibitory effect, then inflammatory signaling could be attenuated

Extracellular ATP and zinc are co-secreted with insulin and activate multiple P2X purinergic receptor channels expressed by islet beta-cells to potentiate insulin secretion

It is well established that ATP is co-secreted with insulin and zinc from pancreatic beta-cells (β-cells) in response to elevations in extracellular glucose concentration. Despite this knowledge, the physiological roles of extracellular secreted ATP and zinc are ill-defined. We hypothesized that secreted ATP and zinc are autocrine purinergic signaling molecules that activate P2X purinergic receptor (P2XR) channels expressed by β-cells to enhance glucose-stimulated insulin secretion (GSIS). To test this postulate, we performed ELISA assays for secreted insulin at fixed time points within a “real-time” assay and confirmed that the physiological insulin secretagogue glucose stimulates secretion of ATP and zinc into the extracellular milieu along with insulin from primary rat islets. Exogenous ATP and zinc alone or together also induced insulin secretion in this model system. Most importantly, the presence of an extracellular ATP scavenger, a zinc chelator, and P2 receptor antagonists attenuated GSIS. Furthermore, mRNA and protein were expressed in immortalized β-cells and primary islets for a unique subset of P2XR channel subtypes, P2X2, P2X3, P2X4, and P2X6, which are each gated by extracellular ATP and modulated positively by extracellular zinc. On the basis of these results, we propose that, within endocrine pancreatic islets, secreted ATP and zinc have profound autocrine regulatory influence on insulin secretion via ATP-gated and zinc-modulated P2XR channels