Snyder G L, Allen P B, Fienberg A A, Valle C G, Huganir R L, Nairn A C, Greengard P
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, New York 10021, USA.
J Neurosci. 2000 Jun 15;20(12):4480-8. doi: 10.1523/JNEUROSCI.20-12-04480.2000.
The activation of cAMP-dependent protein kinase regulates the physiological activity of AMPA-type glutamate receptors. In this study, phosphorylation of the AMPA receptor subunit GluR1 at Ser(845) was increased in neostriatal slices by activation of D1-type dopamine receptors and by inhibitors of protein phosphatase 1/protein phosphatase 2A. In contrast, Ser(831), a residue which, when phosphorylated by protein kinase C or calcium/calmodulin-dependent kinase II, increases AMPA receptor channel conductance, was unaffected by either D1 or D2 receptor agonists in neostriatal slices. The phosphorylation of Ser(845), but not Ser(831), was strongly increased in neostriatum in vivo in response to the psychostimulants cocaine and methamphetamine. The effects of dopamine and psychostimulants on the phosphorylation of GluR1 were attenuated in dopamine and cAMP-regulated phosphoprotein M(r) 32 kDa (DARPP-32) knock-out mice. These results identify DARPP-32 and AMPA-type glutamate receptors as likely essential cellular effectors for psychostimulant actions.
环磷酸腺苷（cAMP）依赖性蛋白激酶的激活调节α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）型谷氨酸受体的生理活性。在本研究中，通过激活D1型多巴胺受体以及使用蛋白磷酸酶1/蛋白磷酸酶2A抑制剂，新纹状体切片中AMPA受体亚基GluR1的丝氨酸（Ser）845位点的磷酸化水平升高。相比之下，丝氨酸831位点在被蛋白激酶C或钙/钙调蛋白依赖性激酶II磷酸化后会增加AMPA受体通道电导，而在新纹状体切片中，该位点不受D1或D2受体激动剂的影响。在体内，响应精神兴奋剂可卡因和甲基苯丙胺，新纹状体中Ser845位点的磷酸化水平大幅升高，但Ser831位点未受影响。多巴胺和精神兴奋剂对GluR1磷酸化的作用在多巴胺和cAMP调节的磷蛋白分子量32 kDa（DARPP-32）基因敲除小鼠中减弱。这些结果表明，DARPP-32和AMPA型谷氨酸受体可能是精神兴奋剂作用的重要细胞效应器。
