Berkeley Jennifer L, Levey Allan I
Department of Neurology and the Emory Center for Neurodegenerative Disease, Emory University, Atlanta, Georgia 30322, USA.
Mol Pharmacol. 2003 Jan;63(1):128-35. doi: 10.1124/mol.63.1.128.
Several families of G protein-coupled receptors (GPCR) have been shown to activate extracellular signal-regulated kinase (ERK) in transfected cells and non-neuronal systems. However, little is known about GPCR activation of ERK in brain. Because ERK is an important component in the regulation of synaptic plasticity, in this study we examined ERK activation by three families of GPCR that respond to major neuromodulatory neurotransmitters in the hippocampus. We used an immunocytochemical approach to examine ERK activation by muscarinic acetylcholine (mAChR), metabotropic glutamate (mGluR), and beta-adrenergic (beta-AR) receptors in CA1 neurons of mouse hippocampal slices. Because these GPCR families comprise receptors coupling to each of the major heterotrimeric G proteins, we examined whether ERK activation differs according to G-protein coupling. By using immunocytochemistry, we were able to examine not only whether each family of receptors activates ERK, but also the cellular populations and subcellular distributions of activated ERK. We demonstrated that M1 mAChRs and group I mGluRs, both of which are Gq-coupled receptors, activate ERK in CA1 pyramidal neurons, although activation in response to mAChR is more robust. The G(i/o)-coupled group II mGluRs activate ERK in glia scattered throughout CA1, and Gs-coupled beta-AR receptors activate ERK in scattered interneurons. Thus, we demonstrated that GPCR coupling to Gq, G(i/o), and Gs all activate ERK in the hippocampus, although each does so with unique properties and distributions.
已有研究表明,在转染细胞和非神经元系统中,几个G蛋白偶联受体(GPCR)家族可激活细胞外信号调节激酶(ERK)。然而,关于脑内GPCR对ERK的激活作用,我们了解甚少。由于ERK是调节突触可塑性的重要组成部分,因此在本研究中,我们检测了对海马体中主要神经调质神经递质产生反应的三个GPCR家族对ERK的激活情况。我们采用免疫细胞化学方法检测了毒蕈碱型乙酰胆碱(mAChR)、代谢型谷氨酸(mGluR)和β-肾上腺素能(β-AR)受体在小鼠海马切片CA1神经元中对ERK的激活作用。由于这些GPCR家族包含与每种主要异三聚体G蛋白偶联的受体,因此我们检测了ERK激活是否因G蛋白偶联情况而异。通过免疫细胞化学,我们不仅能够检测每个受体家族是否激活ERK,还能检测激活的ERK的细胞群体和亚细胞分布。我们证明,M1 mAChR和I组mGluR这两种均与Gq偶联的受体,均可在CA1锥体神经元中激活ERK,尽管对mAChR的反应激活更为强烈。与G(i/o)偶联的II组mGluR可在散布于整个CA1的神经胶质细胞中激活ERK,而与Gs偶联的β-AR受体则可在散布的中间神经元中激活ERK。因此,我们证明,GPCR与Gq、G(i/o)和Gs的偶联均可在海马体中激活ERK,尽管每种情况的激活特性和分布都有所不同。