Study of A2A adenosine receptor gene deficient mice reveals that adenosine analogue CGS 21680 possesses no A2A receptor-unrelated lymphotoxicity
Study of A2A adenosine receptor gene deficient mice reveals that adenosine analogue CGS 21680 possesses no A2A receptor-unrelated lymphotoxicity
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DOI：
10.1038/sj.bjp.0703532
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发表时间：
2000-09-01
影响因子：
7.3
通讯作者：
Sitkovsky, MV
中科院分区：
文献类型：
--
作者：
Apasov, SG;Chen, JF;Sitkovsky, MV
1 Cell surface A(2A) adenosine receptor (A(2A)R) mediated signalling affects a variety of important processes and adenosine analogues possess promising pharmacological properties.2 Demonstrating the receptor specificity of potentially lymphotoxic adenosine-based drugs facilitates their development for clinical applications.3 To distinguish between the receptor-dependent and -independent lymphotoxicity and apoptotic activity of adenosine and its analogues we used lymphocytes from A(2A)R-deficient mice.4 Comparison of A(2A)R-expressing (+/+) and A(2A)R-deficient (-/-) cells in cyclic AMP accumulation assays confirmed that the A(2A)R agonist CGS 21680 is indeed selective for A(2A) receptors in T-lymphocytes.5 Incubation of A2AR-expressing thymocytes with extracellular adenosine or CGS 21680 bz vitro results in the death of about 7-15% of thymocytes. In contrast, no death was induced in parallel assays in cells from A(2A)R-deficient mice, providing genetic evidence that CGS 21680 does not display adenosine receptor-independent intracellular cytotoxicity.6 The A(2A) receptor-specific lymphotoxicity of CGS 21650 is also demonstrated in a long-term (6-day) in vitro model of thymocyte positive selection where addition of A(2A)R antagonist ZM 241,385 did block the effects of CGS 21680, allowing the survival of T cells.7 The use of cells from adenosine receptor-deficient animals is proposed as a part of the screening process for potential adenosine-based drugs for their receptor-independent cytotoxicity and lymphotoxicity.
