期刊
FASEB JOURNAL
卷 28, 期 12, 页码 5288-5298出版社
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.14-255885
关键词
detrusor; urinary tract; myography; micturition; mechanotransduction
资金
- U.S. National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health [DK-095922, DK-083299, AI045897, CA164970]
- NATIONAL CANCER INSTITUTE [R21CA164970] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES [P01AI045897] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [K99DK095922, R01DK083299] Funding Source: NIH RePORTER
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 ADP beta S 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 mu M), 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 ecto-nucleotidases 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.
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