Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis
Molecular determinants of melatonin signaling dysfunction in adolescent idiopathic scoliosis
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DOI：
10.1097/blo.0b013e318811f39fa
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发表时间：
2007-09-01
影响因子：
4.2
通讯作者：
Moreau, Alain
中科院分区：
文献类型：
--
作者：
Azeddine, Bouziane;Letellier, Kareen;Moreau, Alain
目前，青少年特发性脊柱侧凸（AIS）是最常见的脊柱侧凸形式，其遗传原因仍不清楚。在许多假说中，涉及褪黑激素缺乏作为 AIS 来源的神经内分泌假说引起了最大的兴趣和争议，因为在大多数研究中没有观察到循环褪黑激素水平下降。此前，我们通过证明 AIS 患者来源的成骨细胞中发生的褪黑激素信号传导功能障碍（与从健康受试者中分离的类似细胞形成对比）来调和褪黑激素在 AIS 中的作用。我们发现，这种差异是由于 AIS 细胞中丝氨酸残基的磷酸化增加影响了通常与褪黑激素细胞表面受体相关的 G 抑制蛋白的活性而引起的。在此，我们根据细胞对褪黑激素 (cAMP) 的反应和不同的蛋白质-蛋白质相互作用对 AIS 患者进行初步分子分类。这些相互作用包括蛋白激酶 C δ (PKC δ) 与 MT2 褪黑激素受体或 PKC δ 与活化蛋白 C 激酶 1 受体之间的相互作用。这一发现可能有助于未来对 AIS 患者进行分子分类。
Presently, the genetic cause of adolescent idiopathic scoliosis (AIS), the most common form of scoliosis, remains unclear. Among many hypotheses, the neuroendocrine hypothesis involving a melatonin deficiency as the source for AIS generated the greatest interest and controversy since no decrease in circulating melatonin level has been observed in a majority of studies. Previously, we have reconciled the role of melatonin in AIS by demonstrating a melatonin signaling dysfunction occurring in osteoblasts derived from AIS patients, which contrasted with similar cells isolated from healthy subjects. We found that this difference is caused in AIS cells by increased phosphorylation of serine residues affecting the activity of G inhibitory proteins normally associated with melatonin cell surface receptors. Here we propose a preliminary molecular classirication of patients with AIS based on the cellular response to the melatonin (cAMP) and distinct protein-protein interactions. These interactions include those between protein kinase C delta (PKC delta) and MT2 melatonin receptors or PKC delta and the receptor for activated protein C kinase 1. This finding could help in future molecular classification of patients with AIS.