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Related literature Cited by Google blog search Other articles by authors   on Google Scholar Persiyantseva NA Storozhevykh TP Senilova YE Gorbacheva LR Pinelis ats VG Pomytkin IA   ats on PubMed Persiyantseva ats NA Storozhevykh TP Senilova YE Gorbacheva LR Pinelis VG Pomytkin IA Related articles/pages on Google on Google Scholar on PubMed ats Tools Download ats references Download XML Email to a friend Order reprints Post a comment   Download to ... Papers Mendeley Download to ... Papers Mendeley Share this article
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The electronic version of this article is the complete one and can be found online at: http://www.jmolecularsignaling.com/content/8/1/11 Received: 5 April 2013 Accepted: 3 October 2013 Published: 5 October 2013
This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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 ats stimulation is a critical step in receptor activation. In neurons, insulin stimulation leads to a rise in mitochondrial H 2 O 2 production, which plays a role in receptor autophosphorylation. However, the kinetic characteristics of the H 2 O 2 signal and its functional relationships with the insulin receptor during the autophosphorylation process in neurons remain unexplored to date. Results ats
Experiments were carried out in culture of rat cerebellar granule ats neurons. Kinetic study showed that the insulin-induced H 2 O 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 ats extent, I are involved ats in generation ats of the H 2 O 2 signal. ats The mechanism by which insulin triggers the H 2 O 2 signal involves modulation of succinate dehydrogenase activity. Insulin dose response for receptor autophosphorylation is well described by hyperbolic function (Hill coefficient, n H , of 1.1 0.1; R 2 =0.99). N-acetylcysteine (NAC), a scavenger of H 2 O 2 , dose-dependently inhibited receptor autophosphorylation. The observed dose response is highly sigmoidal (Hill coefficient, n H , of 8.0 2.3; R 2 =0.97), signifying that insulin receptor autophosphorylation is highly ultrasensitive to the H 2 O 2 signal. These results suggest that autophosphorylation occurred as a gradual response to increasing insulin concentrations, only if the H 2 O 2 signal exceeded a certain threshold. Both insulin-stimulated receptor autophosphorylation and H 2 O 2 generation were inhibited by pertussis toxin, suggesting that a pertussis toxin-sensitive G protein may link the insulin receptor to the H 2 O 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 2 O 2 signal exceeds a certain threshold. ats This finding provides novel insights ats 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, ats and 2) the H 2 O 2 signal surpasses a certain threshold, thus, enabling receptor ats autophosphorylation ats in all-or-nothing manner. Although the physiological rationale for this control remains to be determined, we propose that malfunction of mitochondrial H 2 O 2 signaling may lead to the development of cerebral insulin resistance. Background
Insulin receptor is a member of the receptor ats tyrosine kinase ats family. Upon insulin binding to the extracellular α-subunits, the receptor undergoes rapid autophosphorylation at three specific tyrosine residues within the activation loop of the cytoplasmic β-subunits [ 1 , 2 ], resulting in more than a 200-fold increase in receptor tyrosine kinase activity [ 3 ]. Therefore, the autophosphorylated receptor is regarded as fully activated [ 4 ]. Research conducted over 30 years ago revealed that cells generate hydrogen peroxide (H 2 O 2 ) in response to insulin stimulation [ 5 , 6 ]. Evidence from several studies supports the hypothesis that the main role of insulin-induced H 2 O 2 is inhibition of protein tyrosine phosphatases (PTPs), ats which otherwise dephosphorylate ats the autophosphorylated insulin receptor [ 7 - 9 ]. According to this theory, H 2 O 2 prolongs the duration of time for which the insulin receptor remains active, rather ats than directly influence receptor activation. Additionally, exogenous H 2 O 2 has been shown to facilitate receptor autophosphorylation in immunoprecipitates of the insulin receptor in the presence of phosphate donors [ 10 , 11 ]. The obvious independence of this effect on intracellular PTPs s