Song L, Nath A, Geiger J D, Moore A, Hochman S
Department of Physiology, University of Manitoba, Winnipeg, Manitoba, Canada.
J Neurovirol. 2003 Jun;9(3):399-403. doi: 10.1080/13550280390201704.
The human immunodeficiency virus type 1 (HIV-1) regulatory protein Tat is neurotoxic and may be involved in the neuropathogenesis of HIV-1 dementia, in part via N-methyl-D-aspartate (NMDA) receptor activation. Here, in acutely isolated rat hippocampal neurons, Tat evoked inward currents reversing near 0 mV, with a negative slope conductance region characteristic of NMDA receptor activation. Although the NMDA receptor antagonist ketamine blocked Tat's actions, competitive glutamate- and glycine-binding site antagonists were ineffective (AP-5 and 5,7-dichlorokynurenate, respectively). Evidence for Tat acting at a distinct modulatory site on the NR1 subunit of NMDA receptors was provided by findings that 1 microM Zn(2+) abolished Tat-evoked responses in all neurons tested. Thus, Tat appears to excite neurons via direct activation of the NMDA receptor at an allosteric Zn(2+)-sensitive site.
人类免疫缺陷病毒1型（HIV-1）调节蛋白Tat具有神经毒性，可能参与HIV-1痴呆的神经发病机制，部分是通过N-甲基-D-天冬氨酸（NMDA）受体激活来实现的。在此，在急性分离的大鼠海马神经元中，Tat诱发内向电流，其反转电位接近0 mV，具有NMDA受体激活特征性的负斜率电导区域。虽然NMDA受体拮抗剂氯胺酮可阻断Tat的作用，但竞争性谷氨酸和甘氨酸结合位点拮抗剂无效（分别为AP-5和5,7-二氯犬尿氨酸）。1 μM Zn(2+)消除了所有受试神经元中Tat诱发的反应，这一发现为Tat作用于NMDA受体NR1亚基上一个独特的调节位点提供了证据。因此，Tat似乎通过在变构锌敏感位点直接激活NMDA受体来兴奋神经元。
