Insulin insulin-like growth factor-I hybrid receptors with high affinity for insulin are developmentally regulated during neurogenesis
Insulin insulin-like growth factor-I hybrid receptors with high affinity for insulin are developmentally regulated during neurogenesis
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DOI：
10.1210/en.140.1.233
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发表时间：
1999-01-01
期刊：
影响因子：
4.8
通讯作者：
de Pablo, F
中科院分区：
文献类型：
--
作者：
García-de Lacoba, M;Alarcón, C;de Pablo, F
胰岛素受体（IR）和胰岛素样生长因子- 1受体（IGFR）信使rna在中枢神经系统发育过程中的广泛共定位，以及胰岛素和igf - 1在神经发生中的作用，提出了阶段特异性和因子特异性信号传导如何发生的问题。因此，有必要对体内存在的受体蛋白进行表征，以开始解决这一问题。在这里，我们研究了第6天（E6）的鸡胚胎神经视网膜，当时它主要是增殖的，在E12，当神经元分化进展。在E6和E12处检测到胰岛素和IGF-I受发育调节的高亲和力结合位点。在增殖性神经视网膜中，对IGF-I具有最高亲和力的典型IGFR与独立的非典型胰岛素结合位点共存，这些非典型胰岛素结合位点对胰岛素和IGF-I具有相似的高亲和力。配体交联受体与IR α亚基、IR β亚基或IGFR β亚基特异性抗体的免疫沉淀证明了IR/IGFR杂交体的存在。它们在E6视网膜中比在E12视网膜中更丰富。在示踪剂浓度下，这些杂交受体结合了大多数放射性标记胰岛素，但很少结合放射性标记的igf - 1。在E12，胰岛素结合位点的特异性发生了变化，它更接近肝脏中的IR，在肝脏中无法检测到杂交体。这些非典型杂交受体的基础自磷酸化水平很高，尽管胰岛素和IGF-I适度地增加了95和105 kDa的两个IR β亚基的磷酸化。高亲和性/低鉴别性的IR/IGFR杂交体主要存在于神经发生的增殖阶段，可以介导胰岛素原和胰岛素的作用，这在该阶段的器官培养中已经得到证实。更重要的是，这种杂交受体可能在生理上与早期神经发生中发现的局部产生的胰岛素原的作用有关。
The extensive colocalization of insulin receptor (IR) and insulinlike growth factor-I receptor (IGFR) messenger RNAs during central nervous system development, together with the effects of insulin and IGF-I in neurogenesis, raises the question of how stage- and factor-specific signaling occurs. Thus, it is necessary to characterize the receptor proteins present in vivo to start addressing this issue. Here we have studied the chick embryonic neuroretina at day 6 (E6), when it is predominantly proliferative, and at E12, when neuronal differentiation is advanced. Developmentally regulated high-affinity binding sites for both insulin and IGF-I were detected at E6 and E12. In proliferative neuroretina, typical IGFR with the highest affinity for IGF-I coexisted with separate atypical insulin binding sites, which had similar high affinity for insulin and IGF-I. Immunoprecipitation of ligand-cross-linked receptors with specific antibodies for the IR alpha-subunit, the IR beta-subunit, or the IGFR beta-subunit demonstrated the presence of IR/IGFR hybrids. They were more abundant in E6 than in E12 retina. These hybrid receptors bound most of radiolabeled insulin, but little radiolabeled IGF-I, at tracer concentrations. At E12, the specificity of the insulin binding sites changed, and it was closer to that found with IR in liver, where hybrids were undetectable. The basal autophosphorylation level of these atypical hybrid receptors was high, although insulin and, even more so, IGF-I modestly increased the phosphorylation of two IR beta-subunits of 95 and 105 kDa. The high-affinity/low-discriminative IR/IGFR hybrids predominantly found in a proliferative stage of neurogenesis can mediate the effects of proinsulin and insulin, previously demonstrated in organoculture at this stage. More importantly, this hybrid receptor may be physiologically relevant for the action of the locally produced proinsulin found in early neurogenesis.