Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism.
Clearance of rapid adenosine release is regulated by nucleoside transporters and metabolism.
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DOI：
10.1002/prp2.189
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发表时间：
2015-12
影响因子：
2.6
通讯作者：
Venton BJ
中科院分区：
文献类型：
--
作者：
Nguyen MD;Ross AE;Ryals M;Lee ST;Venton BJ
腺苷是一种神经调节剂，调节大脑和中枢神经系统的神经传递。最近，在小鼠脊髓切片和麻醉大鼠脑中发现了自发释放的腺苷，这种释放在3-4秒内被清除。本文测定了大鼠尾壳核自发腺苷的清除和脑片外源性腺苷的清除，其Vmax为1.40±0.1kmol.moL/L/秒。在体内，平衡核苷转运蛋白1(Ent1)抑制剂S-(4-硝基苄基)-6-硫代肌苷(NBTI)(1 mg/kg，i.p.)显著延长腺苷的持续时间，而ENT1/2抑制剂双嘧达莫(10 mg/kg)不影响持续时间。腺苷激酶抑制剂5‐(3‐Bromophenyl)‐7‐[6‐(4‐morpholinyl)‐3‐pyrido[2，3‐d]byrimidin‐4‐amine-702(5 mg/kg，i.p.)可延长腺苷的自发释放时间。腺苷脱氨酶抑制剂赤藓-9-(2-羟基-3-壬基)腺嘌呤(EHNA)(10 mg/kg，i.p.)也可延长体内持续时间。同样，NBTI(10μ摩尔/L)、ABT-702(100μ摩尔/L)或EHNA(20摩尔/L)也降低外源性应用腺苷在脑片中的清除率。分别阻断ENT1、腺苷激酶或腺苷脱氨酶的持续时间的增加是相似的，在体内约0.4秒；因此，腺苷的快速清除通过三种具有类似效果的机制发生。ABT-702、NBTI和eHNA的鸡尾酒显著增加了0.7秒的持续时间，因此这些机制不是相加的，可能存在额外的机制在快速的时间尺度上清除腺苷。在几秒的时间尺度上存在多种腺苷清除机制，这表明腺苷在细胞外空间受到严格的调控。
Adenosine is a neuromodulator that regulates neurotransmission in the brain and central nervous system. Recently, spontaneous adenosine release that is cleared in 3–4 sec was discovered in mouse spinal cord slices and anesthetized rat brains. Here, we examined the clearance of spontaneous adenosine in the rat caudate‐putamen and exogenously applied adenosine in caudate brain slices. The V max for clearance of exogenously applied adenosine in brain slices was 1.4 ± 0.1 μmol/L/sec. In vivo, the equilibrative nucleoside transport 1 (ENT1) inhibitor, S‐(4‐nitrobenzyl)‐6‐thioinosine (NBTI) (1 mg/kg, i.p.) significantly increased the duration of adenosine, while the ENT1/2 inhibitor, dipyridamole (10 mg/kg, i.p.), did not affect duration. 5‐(3‐Bromophenyl)‐7‐[6‐(4‐morpholinyl)‐3‐pyrido[2,3‐d]byrimidin‐4‐amine dihydrochloride (ABT‐702), an adenosine kinase inhibitor (5 mg/kg, i.p.), increased the duration of spontaneous adenosine release. The adenosine deaminase inhibitor, erythro‐9‐(2‐hydroxy‐3‐nonyl)adenine (EHNA) (10 mg/kg, i.p.), also increased the duration in vivo. Similarly, NBTI (10 μmol/L), ABT‐702 (100 nmol/L), or EHNA (20 μmol/L) also decreased the clearance rate of exogenously applied adenosine in brain slices. The increases in duration for blocking ENT1, adenosine kinase, or adenosine deaminase individually were similar, about 0.4 sec in vivo; thus, the removal of adenosine on a rapid time scale occurs through three mechanisms that have comparable effects. A cocktail of ABT‐702, NBTI, and EHNA significantly increased the duration by 0.7 sec, so the mechanisms are not additive and there may be additional mechanisms clearing adenosine on a rapid time scale. The presence of multiple mechanisms for adenosine clearance on a time scale of seconds demonstrates that adenosine is tightly regulated in the extracellular space.