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Extracellular UDP potentiates bladder purinergic signaling and smooth muscle contractility via P2Y6 activation of PLC/IP3 pathway
Author(s) -
Yu Weiqun,
Sun Xiaofeng,
Robson Simon C.,
Hill Warren G.
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.923.2
Subject(s) - purinergic receptor , contractility , ppads , p2y receptor , purinergic signalling , microbiology and biotechnology , p2 receptor , chemistry , phospholipase c , endocrinology , agonist , overactive bladder , signal transduction , extracellular , medicine , receptor , biology , adenosine receptor , pathology , alternative medicine
Abnormal bladder smooth muscle (BSM) contractility is critical to the disease process in overactive bladder, incontinence and spinal cord injury. Purinergic signaling comprises a key pathway in modulating BSM contractility but mechanisms remain unclear. We now demonstrate that P2Y 6 , a specific receptor for UDP, is present on mouse BSM cells by immunolocalization. Activation of P2Y 6 by either UDP or a specific agonist (MRS2693) induced a sustained increase in BSM tone (up to 2 mN) in a dose‐dependent manner. Significantly, activation of P2Y 6 , enhanced ATP‐mediated BSM contractile force by up to 45%, indicating synergistic crosstalk between P2X and P2Y signaling. P2Y 6 ‐activated responses were abolished by PLC and IP 3 receptor antagonists U73122 and Xestospongin C, demonstrating involvement of the PLC/IP 3 pathway. Mice lacking Entpd1, an ectonucleotidase on BSM, demonstrated increased P2Y 6 expression (140%), and increased force generation upon P2Y 6 activation (150%). Thus, in vivo perturbations to purinergic signaling resulted in altered P2Y 6 activity and bladder contractility. Therefore, P2Y 6 regulates BSM tone and in doing so selectively maximizes P2X 1 ‐mediated contraction forces. This novel purinergic receptor pathway may play an important role in urinary voiding disorders characterized by abnormal bladder motility. Supported by NIH Grants DK083299 to WGH and P01‐HL076540 & R01‐HL094400 to SCR.