Mitochondrial H sub(2)O sub(2) as an enable signal for triggering autophosphorylation of insulin receptor in neurons

• Published in: Journal of molecular signaling Vol. 8; no. 1; p. 11
• Main Authors: Persiyantseva, Nadezhda A, Storozhevykh, Tatiana P, Senilova, Yana E, Gorbacheva, Lubov R, Pinelis, Vsevolod G, Pomytkin, Igor A
• Format: Journal Article
• Language: English
• Published: 01.01.2013
• Subjects: Acetylcysteine
• ISSN: 1750-2187; 1750-2187
• DOI: 10.1186/1750-2187-8-11

Background: Insulin receptors are widely distributed in the brain, where they play roles in synaptic function, memory formation, and neuroprotection. Autophosphorylation of the receptor in response to insulin stimulation is a critical step in receptor activation. In neurons, insulin stimulation leads to a rise in mitochondrial H sub(2)O sub(2) production, which plays a role in receptor autophosphorylation. However, the kinetic characteristics of the H sub(2)O sub(2) signal and its functional relationships with the insulin receptor during the autophosphorylation process in neurons remain unexplored to date. Results: Experiments were carried out in culture of rat cerebellar granule neurons. Kinetic study showed that the insulin-induced H sub(2)O sub(2) signal precedes receptor autophosphorylation and represents a single spike with a peak at 5-10 s and duration of less than 30 s. Mitochondrial complexes II and, to a lesser extent, I are involved in generation of the H sub(2)O sub(2) signal. The mechanism by which insulin triggers the H sub(2)O sub(2) signal involves modulation of succinate dehydrogenase activity. Insulin dose-response for receptor autophosphorylation is well described by hyperbolic function (Hill coefficient, n sub(H), of 1.1 plus or minus 0.1; R super(2)=0.99). N-acetylcysteine (NAC), a scavenger of H sub(2)O sub(2), dose-dependently inhibited receptor autophosphorylation. The observed dose response is highly sigmoidal (Hill coefficient, n sub(H), of 8.0 plus or minus 2.3; R super(2)=0.97), signifying that insulin receptor autophosphorylation is highly ultrasensitive to the H sub(2)O sub(2) signal. These results suggest that autophosphorylation occurred as a gradual response to increasing insulin concentrations, only if the H sub(2)O sub(2) signal exceeded a certain threshold. Both insulin-stimulated receptor autophosphorylation and H sub(2)O sub(2) generation were inhibited by pertussis toxin, suggesting that a pertussis toxin-sensitive G protein may link the insulin receptor to the H sub(2)O sub(2)-generating system in neurons during the autophosphorylation process. Conclusions: In this study, we demonstrated for the first time that the receptor autophosphorylation occurs only if mitochondrial H sub(2)O sub(2) signal exceeds a certain threshold. This finding provides novel insights into the mechanisms underlying neuronal response to insulin. The neuronal insulin receptor is activated if two conditions are met: 1) insulin binds to the receptor, and 2) the H sub(2)O sub(2) signal surpasses a certain threshold, thus, enabling receptor autophosphorylation in all-or-nothing manner. Although the physiological rationale for this control remains to be determined, we propose that malfunction of mitochondrial H sub(2)O sub(2) signaling may lead to the development of cerebral insulin resistance.