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AMP579 binds to adenosine A 2b receptors thus resolving longstanding mystery of its cardioprotective signaling
Author(s) -
Liu Yanping,
Yang XiMing,
Walker Sheree,
Yang Xiulan,
Cohen Michael V,
Downey James M
Publication year - 2009
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.23.1_supplement.793.24
Subject(s) - agonist , adenosine , receptor , phosphorylation , cardioprotection , antagonist , ischemia , reperfusion injury , mapk/erk pathway , pharmacology , adenosine receptor , chemistry , microbiology and biotechnology , infarction , medicine , myocardial infarction , biology
The mixed A 1 /A 2a adenosine agonist AMP579 given at reperfusion is very protective in animal models of myocardial infarction; however, neither A 1 ‐ nor A 2a ‐selective agonists can duplicate its protection despite blocking studies indicating that the protection came from an A 2 ‐type receptor. We recently noted that A 2b ‐selective agonists are very protective and wondered whether AMP579 might also be an A 2b agonist. AMP579 (500nM) for 1h starting at reperfusion protected isolated rabbit hearts exposed to 30 min‐regional ischemia/2h‐reperfusion (12.9±2.2% infarction of risk zone vs 32.0±1.9% in control hearts). A highly selective A 2b antagonist PSB1115 (500nM) given for the first 15 min of reperfusion blocked AMP579's protection (32.2±3.1% infarction). We then confirmed A 2b binding of AMP579 in human embryonic kidney cells transfected with human A 2b receptors in which A 2b occupation causes phosphorylation of ERK. AMP579 induced ERK phosphorylation with an EC 50 of 250nM. These studies resolve a longstanding mystery related to AMP579's mechanism of protection, and further support the primacy of adenosine A 2b receptors in the cardioprotective signaling that can be implemented at reperfusion. Supported by HL‐20648