N-METHYL-D-ASPARTATE RECEPTOR ACTIVATION INCREASES CAMP LEVELS AND VOLTAGE-GATED CA2+ CHANNEL ACTIVITY IN AREA CA1 OF HIPPOCAMPUS
N-METHYL-D-ASPARTATE RECEPTOR ACTIVATION INCREASES CAMP LEVELS AND VOLTAGE-GATED CA2+ CHANNEL ACTIVITY IN AREA CA1 OF HIPPOCAMPUS
复制标题
DOI：
10.1073/pnas.88.15.6467
复制
发表时间：
1991-08-01
影响因子：
11.1
通讯作者：
SWEATT, JD
中科院分区：
文献类型：
--
作者：
CHETKOVICH, DM;GRAY, R;SWEATT, JD
强直刺激Schaffer侧支输入到海马CA1区可激活N-甲基-D-天冬氨酸(NMDA)受体，这一效应有助于在该区域诱导长时程增强(LTP)。目前的研究表明，LTP刺激大鼠海马区CA1区可引起cAMP水平升高。NMDA受体拮抗剂DL-2-氨基-5-膦戊酸(APV)可阻断cAMP的升高。NMDA还可引起CA1内cAMP的升高，这种作用可被APV和细胞外钙的清除所阻断。这些结果表明，激活NMDA受体可引起钙依赖的cAMP升高，结合强直刺激的数据，提示NMDA受体介导的cAMP增加可能在CA1区LTP的诱导中起作用。CAMP的作用之一可能是增加通过电压门控钙通道的钙内流，因为观察到8-溴-cAMP或NMDA的应用都增加了CA1锥体细胞高阈值钙通道的开放时间。我们的结果提出了在CA1区存在钙离子内流的正反馈回路的可能性。在该模型中，NMDA受体介导的钙内流通过cAMP增加和随后电压门控钙通道活性增加的中间步骤导致进一步的钙内流增加。
Tetanic stimulation of the Schaffer collateral inputs into area CA1 of the hippocampus causes N-methyl-D-aspartate (NMDA) receptor activation, an effect that contributes to the induction of long-term potentiation (LTP) in this region. The present studies demonstrate that LTP-inducing tetanic stimulation in rat hippocampal area CA1 elicited increased levels of cAMP. The elevation of cAMP was blocked by the NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (APV). Bath application of NMDA also resulted in an increase in cAMP in CA1, an effect that was blocked by both APV and removal of extracellular Ca2+. These findings suggest that activation of NMDA receptors elicits a Ca2+-dependent increase in cAMP, and taken together with the data from tetanic stimulation, suggest that NMDA-receptor-mediated increases in cAMP could play a role in the induction of LTP in area CA1. One role for cAMP may be to increase Ca2+ influx through voltage-gated Ca2+ channels, as it was observed that application of either 8-bromo-cAMP or NMDA increased the fractional open time of high-threshold Ca2+ channels in CA1 pyramidal cells. Our results raise the possibility that a positive-feedback loop for Ca2+ influx in area CA1 exists. In this model, NMDA receptor-mediated Ca2+ influx leads to an enhancement of further Ca2+ influx via intermediate steps of increased cAMP and subsequent increased voltage-gated Ca2+ channel activity.