ATP and purinergic receptor–dependent membrane traffic in bladder umbrella cells
Edward C.Y. Wang, … , Lori A. Birder, Gerard Apodaca
Edward C.Y. Wang, … , Lori A. Birder, Gerard Apodaca
Published September 1, 2005
Citation Information: J Clin Invest. 2005;115(9):2412-2422. https://doi.org/10.1172/JCI24086.
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Research Article Cell biology

ATP and purinergic receptor–dependent membrane traffic in bladder umbrella cells

Abstract

The umbrella cells that line the bladder are mechanosensitive, and bladder filling increases the apical surface area of these cells; however, the upstream signals that regulate this process are unknown. Increased pressure stimulated ATP release from the isolated uroepithelium of rabbit bladders, which was blocked by inhibitors of vesicular transport, connexin hemichannels, ABC protein family members, and nucleoside transporters. Pressure-induced increases in membrane capacitance (a measure of apical plasma membrane surface area where 1 μF ≈ 1 cm2) were inhibited by the serosal, but not mucosal, addition of apyrase or the purinergic receptor antagonist PPADS. Upon addition of purinergic receptor agonists, increased capacitance was observed even in the absence of pressure. Moreover, knockout mice lacking expression of P2X2 and/or P2X3 receptors failed to show increases in apical surface area when exposed to hydrostatic pressure. Treatments that prevented release of Ca2+ from intracellular stores or activation of PKA blocked ATPγS-stimulated changes in capacitance. These results indicate that increased hydrostatic pressure stimulates release of ATP from the uroepithelium and that upon binding to P2X and possibly P2Y receptors on the umbrella cell, downstream Ca2+ and PKA second messenger cascades may act to stimulate membrane insertion at the apical pole of these cells.

Authors

Edward C.Y. Wang, Jey-Myung Lee, Wily G. Ruiz, Elena M. Balestreire, Maximilian von Bodungen, Stacey Barrick, Debra A. Cockayne, Lori A. Birder, Gerard Apodaca

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Figure 8

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Model for ATP and purinergic receptor–regulated exocytosis/endocytosis i...
Model for ATP and purinergic receptor–regulated exocytosis/endocytosis in bladder umbrella cells. The accumulation of urine in the bladder increases hydrostatic pressure, stimulating release of ATP from uroepithelium (step 1) and possibly other adjacent cell types (not shown). ATP release may occur through multiple mechanisms, including vesicular release, conductance of ATP though ABC or nucleoside transporters, or movement of ATP across connexin hemichannels. The serosally released ATP may bind to P2X3-containing receptors present on afferent nerve processes (step 2), increasing nerve firing and relaying bladder filling to the CNS (step 3). Serosally released ATP may also bind to receptors containing P2X2 and/or P2X3 subunits present on the uroepithelium, including the basolateral surface of the umbrella cell layer (step 4). Other receptors, including P2X or P2Y receptor isoforms, are also present on the serosal surface of the epithelium and may also be stimulated by ATP (or other released or processed nucleotides/nucleosides). Ligand binding causes increased levels of cytoplasmic Ca2+ (a result of Ca2+ influx from outside the cell and efflux from intracellular stores) and activation of PKA that induces apical membrane turnover including discoidal/fusiform vesicle exocytosis and endocytosis (step 5). Although in the simplest model, ATP binds to purinergic receptors on the umbrella cell layer, it remains possible that ATP binds to purinergic receptors present on basal/intermediate cells (step 6), or other cell types, to signal the release of unidentified secretagogues that act upon umbrella cells to stimulate vesicle exocytosis (step 7). For simplicity, mucosal purinergic signaling events are not shown; however, these could be important in modulating the signaling pathways that initiate at the serosal surface of the umbrella cells.