INSULIN-RECEPTOR AUTOPHOSPHORYLATION AND SIGNALING IS ALTERED BY MODULATION OF MEMBRANE PHYSICAL-PROPERTIES

Many membrane functions are modulated by the bulk biophysical properti es of the membrane. Various compounds which alter membrane physical pr operties were investigated for their ability to modulate insulin recep tor autophosphorylation and signaling. Compounds which raise the bilay er to hexagonal phase transition temperature in model membranes, inclu ding carbobenzoxydipeptides, apolipoprotein A-I, acyl carnitines, and lysophosphatidylcholine, inhibited insulin stimulation of insulin rece ptor tyrosine phosphorylation of isolated receptors as well as in cell s overexpressing human insulin receptor. For compounds of similar stru cture, the inhibition of insulin receptor tyrosine phosphorylation cor relates well with their bilayer-stabilizing potency. Most of the compo unds which inhibit tyrosine phosphorylation of the insulin receptor al so inhibited glucose uptake in the same cells. Compounds which lower t he bilayer to hexagonal phase transition temperature in model membrane s enhanced insulin stimulation of autophosphorylation in isolated rece ptors, with no effect on insulin receptor activity in NIH 3T3 HIR 3.5 cells. The effects of cationic amphiphiles were not readily predictabl e 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 recep tor. This provides evidence that mechanism of modulation of insulin si gnaling by these additives lies in their ability to alter the bulk phy sical properties of the membrane. The results suggest that membrane mo nolayer curvature strain is a factor contributing to the efficiency of insulin signal transduction.