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ADP‐induced bladder contractility is mediated by P2Y 12 receptor and temporally regulated by ectonucleotidases and adenosine signaling
Author(s) -
Yu Weiqun,
Sun Xiaofeng,
Robson Simon C.,
Hill Warren G.
Publication year - 2014
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/fj.14-255885
Subject(s) - purinergic receptor , adenosine , contractility , p2y receptor , purinergic signalling , contraction (grammar) , p2y12 , ppads , p2 receptor , adenosine receptor antagonist , adenosine receptor , muscle contraction , chemistry , pharmacology , adenosine diphosphate , adenosine triphosphate , receptor , microbiology and biotechnology , biology , medicine , endocrinology , platelet , agonist , biochemistry , platelet aggregation
Purinergic signaling comprises one key pathway in modulating bladder smooth muscle (BSM) contractility, disorders of which become highly prevalent with aging. ADP was first observed to modulate BSM contractility >40 yr ago, yet the underlying molecular mechanism still remains unclear. Here, we demonstrate, using myography, that ADP and ADPβS dose‐dependently induce mouse BSM contraction, and ADP‐induced BSM contraction is blocked by a selective P2Y 12 receptor (P2Y 12 R) antagonist, PSB 0739 (25 μM), but is unaffected by P2Y 1 and P2Y 13 receptor antagonists. P2Y 12 R in BSM exhibits distinct pharmacological properties that are different from P2Y 12 R in platelets. After an immediate contraction, prolonged exposure to ADP causes BSM to become refractory to further ADP‐mediated contraction. However, in mice lacking ectonucleotidases Entpd1 (ATP→ADP→AMP) or Nt5e (AMP→adenosine), or by inhibiting adenosine signaling, the refractory response was altered, resulting in repeated BSM contractions in response to repeated ADP (0.1‐1 mM) stimulation. Our data indicate that P2Y 12 R undergoes slow desensitization; ADP‐P2Y 12 signaling is tightly regulated by Entpd1/Nt5e activity and adenosine receptors; and ADP‐adenosine signaling play an important role in modulating P2X‐mediated BSM contraction. The identification of P2Y 12 R in BSM, and the current clinical availability of P2Y 12 R inhibitors, such as clopidogrel, offers potentially novel treatment strategies for bladder contractility disorders.—Yu, W., Sun, X., Robson, S. C., Hill, W. G., ADP‐induced bladder contractility is mediated by P2Y12 receptor and temporally regulated by ectonucleotidases and adenosine signaling. FASEB J. 28, 5288–5298 (2014). www.fasebj.org