绑定的特点levetiracetam突触囊泡蛋白2 (SV2A)在人类大脑和CHO细胞表达人类的重组蛋白。

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吉拉德M,城主P, B的福娃

绑定的特点levetiracetam突触囊泡蛋白2 (SV2A)在人类大脑和CHO细胞表达人类的重组蛋白。

欧元J杂志。2006年4月24日,536 (2):102 - 8。Epub 2006 3月10。

PubMed ID
16556440 (在PubMed
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文摘

抗癫痫药物levetiracetam特定结合位点(2 s - (oxo-1-pyrrolidinyl) butanamide Keppra)在老鼠大脑,称为levetiracetam结合位点,是几年前发现的。最近,这种结合位点已被确认为突触囊泡蛋白2 (SV2A),一种蛋白质存在于突触囊泡(林奇,B。Lambeng, N。Nocka, K。Kensel-Hammes, P。Bajjalieh,克里Matagne,。福娃,B。,2004年。突触囊泡蛋白的结合位点是SV2A levetiracetam抗癫痫药物。Proc。国家的。学会科学。美国,101年,9861 - 9866。]。在这项研究中,我们为特征的绑定属性levetiracetam事后人类大脑和比较人类SV2A表示在中国仓鼠卵巢(CHO)细胞。结果表明,绑定属性levetiracetam [3 h]近30889,以前的模拟特征作为levetiracetam合适的配体结合位点/ SV2A老鼠大脑(吉拉德,M。福娃,B。米歇尔,P。, Vertongen, P., Massingham, R. Chatelain, P., 2003. Binding characteristics of [3H]ucb 30889 to levetiracetam binding sites in rat brain. Eur. J. Pharmacol. 478, 1-9.], are almost identical in human brain samples (cerebral cortex, hippocampus and cerebellum) and in CHO cell membranes expressing the human SV2A protein. Moreover, the results are also similar to those previously obtained in rat brain. [3H]ucb 30889 binding in human brain and to SV2A was saturable and reversible. At 4 degrees C, its binding kinetics were best fitted assuming a two-phase model in all tissues. The half-times of association for the fast component ranged between 1 to 2 min and represent 30% to 36% of the sites whereas the half-times for the slow component ranged from 20 to 29 min. In dissociation experiments, the half-times were from 2 to 4 min for the fast component (33% to 49% of the sites) and 20 to 41 min for the slow component. Saturation binding curves led to Kd values for [3H]ucb 30889 of 53+/-7, 55+/-9, 70+/-11 and 75+/-33 nM in human cerebral cortex, hippocampus, cerebellum and CHO cells expressing SV2A respectively. Bmax values around 3-4 pmol/mg protein were calculated in all brain regions. Some of the saturation curves displayed curvilinear Scatchard plots indicating the presence of high and low affinity binding sites. When this was the case, Kd values from 25 to 30 nM for the high affinity sites (24% to 34% of total sites) and from 200 to 275 nM for the low affinity sites were calculated. This was observed in all brain regions and in CHO cell membranes expressing the SV2A protein. It cannot be explained by putative binding of [3H]ucb 30889 to SV2B or C isoforms but may reflect different patterns of SV2A glycosylation or the formation of SV2A oligomers. Competition experiments were performed to determine the affinities for SV2A of a variety of compounds including levetiracetam, some of its analogues and other molecules known to interact with levetiracetam binding sites in rat brain such as bemegride, pentylenetetrazol and chlordiazepoxide. We found an excellent correlation between the affinities of these compounds measured in human brain, rat brain and CHO cells expressing human SV2A. In conclusion, we report for the first time that the binding characteristics of native levetiracetam binding sites/SV2A in human brain and rat brain share very similar properties with human recombinant SV2A expressed in CHO cells.

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