McCallum C D, Epand R M
Department of Biochemistry, Health Science Centre, West Hamilton, Ontario, Canada.
Biochemistry. 1995 Feb 14;34(6):1815-24. doi: 10.1021/bi00006a001.
Many membrane functions are modulated by the bulk biophysical properties of the membrane. Various compounds which alter membrane physical properties were investigated for their ability to modulate insulin receptor autophosphorylation and signaling. Compounds which raise the bilayer to hexagonal phase transition temperature in model membranes, including carbobenzoxydipeptides, apolipoprotein A-I, acyl carnitines, and lysophosphatidylcholine, inhibited insulin stimulation of insulin receptor tyrosine phosphorylation of isolated receptors as well as in cells overexpressing human insulin receptor. For compounds of similar structure, the inhibition of insulin receptor tyrosine phosphorylation correlates well with their bilayer-stabilizing potency. Most of the compounds which inhibit tyrosine phosphorylation of the insulin receptor also inhibited glucose uptake in the same cells. Compounds which lower the bilayer to hexagonal phase transition temperature in model membranes enhanced insulin stimulation of autophosphorylation in isolated receptors, with no effect on insulin receptor activity in NIH 3T3 HIR 3.5 cells. The effects of cationic amphiphiles were not readily predictable from their membrane modulating activity. All of the compounds tested exert their effects independent of changes in insulin binding to the receptor or changes in the basal tyrosine kinase activity of the receptor. This provides evidence that mechanism of modulation of insulin signaling by these additives lies in their ability to alter the bulk physical properties of the membrane. The results suggest that membrane monolayer curvature strain is a factor contributing to the efficiency of insulin signal transduction.
许多膜功能是由膜的整体生物物理性质调节的。研究了各种改变膜物理性质的化合物调节胰岛素受体自身磷酸化和信号传导的能力。在模型膜中能提高双层到六方相转变温度的化合物，包括苄氧羰基二肽、载脂蛋白A-I、酰基肉碱和溶血磷脂酰胆碱，在分离的受体以及过表达人胰岛素受体的细胞中，均抑制胰岛素对胰岛素受体酪氨酸磷酸化的刺激作用。对于结构相似的化合物，对胰岛素受体酪氨酸磷酸化的抑制作用与其双层稳定能力密切相关。大多数抑制胰岛素受体酪氨酸磷酸化的化合物也抑制相同细胞中的葡萄糖摄取。在模型膜中能降低双层到六方相转变温度的化合物增强了分离受体中自身磷酸化的胰岛素刺激作用，对NIH 3T3 HIR 3.5细胞中的胰岛素受体活性没有影响。阳离子两亲物的作用不能从其膜调节活性轻易预测。所有测试的化合物发挥其作用与胰岛素与受体结合的变化或受体基础酪氨酸激酶活性的变化无关。这提供了证据表明这些添加剂调节胰岛素信号传导的机制在于它们改变膜整体物理性质的能力。结果表明膜单层曲率应变是影响胰岛素信号转导效率的一个因素。
