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

Loss of apical monocilia on collecting duct principal cells impairs ATP secretion across the apical cell surface and ATP-dependent and flow-induced calcium signals

Renal epithelial cells release ATP constitutively under basal conditions and release higher quantities of purine nucleotide in response to stimuli. ATP filtered at the glomerulus, secreted by epithelial cells along the nephron, and released serosally by macula densa cells for feedback signaling to afferent arterioles within the glomerulus has important physiological signaling roles within kidneys. In autosomal recessive polycystic kidney disease (ARPKD) mice and humans, collecting duct epithelial cells lack an apical central cilium or express dysfunctional proteins within that monocilium. Collecting duct principal cells derived from an Oak Ridge polycystic kidney (orpkTg737) mouse model of ARPKD lack a well-formed apical central cilium, thought to be a sensory organelle. We compared these cells grown as polarized cell monolayers on permeable supports to the same cells where the apical monocilium was genetically rescued with the wild-type Tg737 gene that encodes Polaris, a protein essential to cilia formation. Constitutive ATP release under basal conditions was low and not different in mutant versus rescued monolayers. However, genetically rescued principal cell monolayers released ATP three- to fivefold more robustly in response to ionomycin. Principal cell monolayers with fully formed apical monocilia responded three- to fivefold greater to hypotonicity than mutant monolayers lacking monocilia. In support of the idea that monocilia are sensory organelles, intentionally harsh pipetting of medium directly onto the center of the monolayer induced ATP release in genetically rescued monolayers that possessed apical monocilia. Mechanical stimulation was much less effective, however, on mutant orpk collecting duct principal cell monolayers that lacked apical central monocilia. Our data also show that an increase in cytosolic free Ca2+ primes the ATP pool that is released in response to mechanical stimuli. It also appears that hypotonic cell swelling and mechanical pipetting stimuli trigger release of a common ATP pool. Cilium-competent monolayers responded to flow with an increase in cell Ca2+ derived from both extracellular and intracellular stores. This flow-induced Ca2+ signal was less robust in cilium-deficient monolayers. Flow-induced Ca2+ signals in both preparations were attenuated by extracellular gadolinium and by extracellular apyrase, an ATPase/ADPase. Taken together, these data suggest that apical monocilia are sensory organelles and that their presence in the apical membrane facilitates the formation of a mature ATP secretion apparatus responsive to chemical, osmotic, and mechanical stimuli. The cilium and autocrine ATP signaling appear to work in concert to control cell Ca2+. Loss of a cilium-dedicated autocrine purinergic signaling system may be a critical underlying etiology for ARPKD and may lead to disinhibition and/or upregulation of multiple sodium (Na+) absorptive mechanisms and a resultant severe hypertensive phenotype in ARPKD and, possibly, other diseases

Purinergic signaling in the lumen of a normal nephron and in remodeled PKD encapsulated cysts

The nephron is the functional unit of the kidney. Blood and plasma are continually filtered within the glomeruli that begin each nephron. Adenosine 5′ triphosphate (ATP) and its metabolites are freely filtered by each glomerulus and enter the lumen of each nephron beginning at the proximal convoluted tubule (PCT). Flow rate, osmolality, and other mechanical or chemical stimuli for ATP secretion are present in each nephron segment. These ATP-release stimuli are also different in each nephron segment due to water or salt permeability or impermeability along different luminal membranes of the cells that line each nephron segment. Each of the above stimuli can trigger additional ATP release into the lumen of a nephron segment. Each nephron-lining epithelial cell is a potential source of secreted ATP. Together with filtered ATP and its metabolites derived from the glomerulus, secreted ATP and adenosine derived from cells along the nephron are likely the principal two of several nucleotide and nucleoside candidates for renal autocrine and paracrine ligands within the tubular fluid of the nephron. This minireview discusses the first principles of purinergic signaling as they relate to the nephron and the urinary bladder. The review discusses how the lumen of a renal tubule presents an ideal purinergic signaling microenvironment. The review also illustrates how remodeled and encapsulated cysts in autosomal dominant polycystic kidney disease (ADPKD) and remodeled pseudocysts in autosomal recessive PKD (ARPKD) of the renal collecting duct likely create an even more ideal microenvironment for purinergic signaling. Once trapped in these closed microenvironments, purinergic signaling becomes chronic and likely plays a significant epigenetic and detrimental role in the secondary progression of PKD, once the remodeling of the renal tissue has begun. In PKD cystic microenvironments, we argue that normal purinergic signaling within the lumen of the nephron provides detrimental acceleration of ADPKD once remodeling is complete

Post-COVID-19 Syndrome Based on Disease Form and Associated Comorbidities

(1) Background: SARS-CoV-2 has infected more than 97 million people worldwide and caused the death of more than 6 million. (2) Methods: Between 1 October and 31 December 2020, 764 patients diagnosed with SARS-CoV-2 infection were selected based on RT-PCR test results. The following parameters were noted: age, gender, origin, days of hospitalization, COVID-19 experienced form, radiographic imaging features, associated comorbidities, and recommended treatment at discharge. (3) Results: The mean age at the time of COVID-19 infection was 55.2 years for men and 55.3 years for women. There was a similar age distribution among patients, regardless of gender. There was a substantial difference between the average lengths of hospitalization and those with residual symptoms—most patients who reported symptoms after discharge had been admitted with moderately severe forms of illness. Fatigue was the main remaining symptom (36%). (4) Conclusions: In conclusion, to clarify the impact of SARS-CoV-2 infection on patients in the long term, further studies are needed to investigate the elements assessed. Well-designed recovery programs will be needed to effectively manage these patients, with multidisciplinary collaboration and a team of professionals involved in all aspects of post-COVID patient health

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

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