McAvoy Thomas, Zhou Ming-ming, Greengard Paul, Nairn Angus C
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, New York, NY 10021, USA.
Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3531-6. doi: 10.1073/pnas.0813263106. Epub 2009 Feb 13.
Protein kinase A (PKA)-dependent signaling cascades play an important role in mediating the effects of dopamine and other neurotransmitters in striatal medium spiny neurons. We have identified a prominent striatal PKA substrate as Rap1-GTPase activating protein (Rap1GAP), a negative regulator of Rap1 signaling. Although present throughout the brain, Rap1GAP is enriched in striatal medium spiny neurons and is phosphorylated by PKA at Ser-441 and Ser-499 in response to activation of D1 dopamine receptors. Phosphorylation of Rap1GAP is associated with inhibition of GAP activity, as demonstrated by increased Rap1 activity in striatal neurons. Phosphorylation of Rap1GAP is also associated with decreased [corrected] dendritic spine head size in cultured neurons. These findings suggest that phosphorylation of Rap1GAP by PKA plays an important role in striatal neurons by modulating Rap1 actions.
蛋白激酶A（PKA）依赖性信号级联反应在介导多巴胺和其他神经递质对纹状体中等棘状神经元的作用中发挥重要作用。我们已确定一种显著的纹状体PKA底物为Rap1-鸟苷三磷酸酶激活蛋白（Rap1GAP），它是Rap1信号的负调节因子。尽管Rap1GAP在全脑均有表达，但在纹状体中等棘状神经元中含量丰富，并且在D1多巴胺受体激活后，会在丝氨酸-441和丝氨酸-499位点被PKA磷酸化。Rap1GAP的磷酸化与GAP活性的抑制相关，这在纹状体神经元中Rap1活性增加得到了证实。Rap1GAP的磷酸化还与培养神经元中树突棘头部大小的减小相关。这些发现表明，PKA介导的Rap1GAP磷酸化通过调节Rap1的作用在纹状体神经元中发挥重要作用。
