Department of Biological Sciences, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 609-735, Republic of Korea.
Neurosci Lett. 2013 Jun 7;544:147-51. doi: 10.1016/j.neulet.2013.04.003. Epub 2013 Apr 11.
The regulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor GluR1 subunit phosphorylation at serine 845 (GluR1-Ser845) by protein kinase G (PKG) activation was investigated in the nucleus accumbens (NAc) after repeated cocaine administration. Intra-NAc injection of the cyclic guanosine monophosphate (cGMP) analog, Rp-8-Br-PET-cGMPS (5 nmol) and the PKG inhibitor, KT5823 (2 nmol), prior to the final drug injection significantly decreased GluR1-Ser845 phosphorylation elevated by repeated systemic injections of cocaine (20mg/kg) once a day for seven consecutive days. The inhibition of PKG also attenuated Ca(2+)-calmodulin-dependent protein kinases II (CaMKII) phosphorylation, however inhibition of CaMKII with KN62 (20 nmol) did not alter the phosphorylation state of GluR1-Ser845. Similarly, inhibition of cGMP or PKG attenuated the repeated cocaine-induced increase in locomotor activity. These findings suggest that the AMPA receptor provides a PKG-sensitive phosphorylation site on GluR1-Ser845 in the NAc after repeated cocaine, thus contributing to behavioral alterations.
蛋白激酶 G（PKG）激活对反复可卡因给药后伏隔核（NAc）中α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体 GluR1 亚基丝氨酸 845 位（GluR1-Ser845）磷酸化的调节作用进行了研究。在最后一次药物注射前，NAc 内注射环鸟苷单磷酸（cGMP）类似物 Rp-8-Br-PET-cGMPS（5 nmol）和 PKG 抑制剂 KT5823（2 nmol），可显著降低因每日重复系统注射可卡因（20mg/kg）一次而升高的 GluR1-Ser845 磷酸化。PKG 的抑制作用也减弱了钙调蛋白依赖性蛋白激酶 II（CaMKII）的磷酸化，但用 KN62（20 nmol）抑制 CaMKII 并不能改变 GluR1-Ser845 的磷酸化状态。同样，抑制 cGMP 或 PKG 可减弱重复可卡因诱导的运动活性增加。这些发现表明，在反复可卡因后，NAc 中的 AMPA 受体在 GluR1-Ser845 上提供了一个 PKG 敏感的磷酸化位点，从而导致行为改变。
