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首页> 外文期刊>Neurochemistry International: The International Journal for the Rapid Publication of Critical Reviews, Preliminary and Original Research Communications in Neurochemistry >ERK phosphorylation in intact, adult brain by alpha(2)-adrenergic transactivation of EGF receptors.
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ERK phosphorylation in intact, adult brain by alpha(2)-adrenergic transactivation of EGF receptors.

机译：ERK受体的α（2）-肾上腺素反式激活在完整的成人大脑中的ERK磷酸化。

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摘要

Our previous work demonstrated dexmedetomidine-activated phosphorylation of extracellular regulated kinases 1 and 2 (ERK(1/2)) in primary cultures of mouse astrocytes and showed that it is evoked by alpha(2)-adrenoceptor-mediated transactivation of epidermal growth factor (EGF) receptors, a known response to activation of G(i/o)- or G(q)-coupled receptors [Li, B., Du, T., Li, H., Gu, L., Zhang, H., Huang, J., Hertz, L., Peng, L., 2008a. Signaling pathways for transactivation by dexmedetomidine of epidermal growth factor receptors in astrocytes and its paracrine effect on neurons. Br. J. Pharmacol. 154, 191-203]. Like most studies of transactivation, that study used cultured cells, raising the question whether a similar effect can be demonstrated in intact brain tissue and the brain in vivo. In the present study we have shown that (i) dexmedetomidine-mediated ERK(1/2) phosphorylation occurs in mouse brain slices with a similar concentration dependence as in cultured astrocytes (near-maximum effect at 50nM); (ii) intraperitoneal injection of dexmedetomidine (3microg/kg) in adult mice causes rapid phosphorylation of the EGF receptor (at Y845 and Y992) and of ERK(1/2) in the brain; (iii) both EGF receptor and ERK(1/2) phosphorylation are inhibited by intraventricular administration of (a) AG 1478, a specific inhibitor of the receptor-tyrosine kinase of the EGF receptor; (b) GM 6001, an inhibitor of metalloproteinase(s) required for release of EGF receptor agonists from membrane-bound precursors; or (c) heparin, neutralizing heparin-binding EGF (HB-EGF). Thus, in intact brain HB-EGF, known to be expressed in brain, may be the major EGF agonist released in response to stimulation of alpha(2)-adrenoceptors, the released agonist(s) activate(s) EGF receptors, and ERK(1/2) is phosphorylated as a conventional response to EGF receptor activation. Our previous paper (see above) showed that dexmedetomidine evokes no ERK(1/2) phosphorylation in cultured neurons, but neurons respond to astrocyte-conditioned medium (and to EGF) with ERK(1/2) phosphorylation. The present findings therefore suggest that EGF receptor transactivation in astrocytes in the mature brain in vivo is an important process in response to alpha(2)-adrenoceptor stimulation and may lead to phosphorylation of ERK(1/2) both in astrocytes themselves and in adjacent neurons.
机译：我们以前的工作证明了小鼠星形胶质细胞原代培养物中右美托咪定激活的细胞外调节激酶1和2（ERK（1/2））的磷酸化，并表明它是由α（2）-肾上腺素受体介导的表皮生长因子（ EGF）受体，一种已知的激活G（i / o）或G（q）偶联受体的反应[Li，B.，Du，T.，Li，H.，Gu，L.，Zhang，H. ，Huang，J.，Hertz，L.，Peng L.，2008a。右美托咪定使星形胶质细胞中表皮生长因子受体反式激活的信号通路及其对神经元的旁分泌作用。 Br。 J.Pharmacol。 154，191-203]。像大多数反式激活研究一样，该研究也使用了培养的细胞，这引发了一个问题，即能否在完整的脑组织和体内脑中证明类似的作用。在本研究中，我们表明（i）右美托咪定介导的ERK（1/2）磷酸化发生在小鼠脑片中，其浓度依赖性与培养的星形胶质细胞相似（50nM时接近最大作用）; （ii）在成年小鼠腹膜内注射右美托咪定（3microg / kg）会导致大脑中EGF受体（在Y845和Y992处）和ERK（1/2）迅速磷酸化; （iii）EGF受体和ERK（1/2）的磷酸化都受到脑室内给药的抑制。（a）AG 1478，EGF受体的酪氨酸激酶的特异性抑制剂。 （b）GM 6001，一种金属蛋白酶抑制剂，是从膜结合前体释放EGF受体激动剂所必需的; （c）肝素，中和结合肝素的EGF（HB-EGF）。因此，在完整的大脑中，已知在大脑中表达的HB-EGF可能是响应刺激α（2）-肾上腺素受体而释放的主要EGF激动剂，释放的激动剂激活EGF受体和ERK （1/2）被磷酸化为对EGF受体活化的常规反应。我们以前的论文（见上文）显示，右美托咪定在培养的神经元中未引起ERK（1/2）磷酸化，但神经元对星形胶质细胞条件培养基（和EGF）产生ERK（1/2）磷酸化反应。因此，本研究结果表明，成熟脑中体内星形胶质细胞的EGF受体反式激活是响应α（2）-肾上腺素受体刺激的重要过程，并且可能导致星形胶质细胞本身和邻近细胞的ERK（1/2）磷酸化。神经元。

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