Excess adenosine in murine penile erectile tissues contributes to priapism via A2B adenosine receptor signaling.
Priapism, abnormally prolonged penile erection in the absence of sexual excitation, is associated with ischemia-mediated erectile tissue damage and subsequent erectile dysfunction. It is common among males with sickle cell disease (SCD), and SCD transgenic mice are an accepted model of the disorder. Current strategies to manage priapism suffer from a poor fundamental understanding of the molecular mechanisms underlying the disorder. Here we report that mice lacking adenosine deaminase (ADA), an enzyme necessary for the breakdown of adenosine, displayed unexpected priapic activity. ADA enzyme therapy successfully corrected the priapic activity both in vivo and in vitro, suggesting that it was dependent on elevated adenosine levels. Further genetic and pharmacologic evidence demonstrated that A2B adenosine receptor-mediated (A2BR-mediated) cAMP and cGMP induction was required for elevated adenosine-induced prolonged penile erection. Finally, priapic activity in SCD transgenic mice was also caused by elevated adenosine levels and A2BR activation. Thus, we have shown that excessive adenosine accumulation in the penis contributes to priapism through increased A2BR signaling in both Ada -/- and SCD transgenic mice. These findings provide insight regarding the molecular basis of priapism and suggest that strategies to either reduce adenosine or block A2BR activation may prove beneficial in the treatment of this disorder.
Mi
Tiejuan
T
Department of Biochemistry and Molecular Biology, University of Texas Medical School at Houston, Houston, Texas 77030, USA.
Abbasi
Shahrzad
S
Zhang
Hong
H
Uray
Karen
K
Chunn
Janci L
JL
Xia
Ling Wei
LW
Molina
Jose G
JG
Weisbrodt
Norman W
NW
Kellems
Rodney E
RE
Blackburn
Michael R
MR
Xia
Yang
Y
D000241:Adenosine / Q000378:metabolism* / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D006152:Cyclic GMP / Q000096:biosynthesis; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D010410:Penile Erection / Q000187:drug effects; D010413:Penis / Q000033:anatomy & histology / Q000098:blood supply / Q000378:metabolism*; D043704:Receptor, Adenosine A2B / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
D043704:Receptor, Adenosine A2B; D000242:Cyclic AMP; D000243:Adenosine Deaminase; D006152:Cyclic GMP; D000241:Adenosine