J Mol Signal. 2013 Oct 05;8(1):11. doi: 10.1186/1750-2187-8-11.
Mitochondrial H2O2 as an enable signal for triggering autophosphorylation of insulin receptor in neurons.
Journal of molecular signaling
Nadezhda A Persiyantseva, Tatiana P Storozhevykh, Yana E Senilova, Lubov R Gorbacheva, Vsevolod G Pinelis, Igor A Pomytkin
PMID: 24094269
PMCID: PMC3817577 DOI: 10.1186/1750-2187-8-11
Abstract
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 H2O2 production, which plays a role in receptor autophosphorylation. However, the kinetic characteristics of the H2O2 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 H2O2 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 H2O2 signal. The mechanism by which insulin triggers the H2O2 signal involves modulation of succinate dehydrogenase activity. Insulin dose-response for receptor autophosphorylation is well described by hyperbolic function (Hill coefficient, nH, of 1.1±0.1; R2=0.99). N-acetylcysteine (NAC), a scavenger of H2O2, dose-dependently inhibited receptor autophosphorylation. The observed dose response is highly sigmoidal (Hill coefficient, nH, of 8.0±2.3; R2=0.97), signifying that insulin receptor autophosphorylation is highly ultrasensitive to the H2O2 signal. These results suggest that autophosphorylation occurred as a gradual response to increasing insulin concentrations, only if the H2O2 signal exceeded a certain threshold. Both insulin-stimulated receptor autophosphorylation and H2O2 generation were inhibited by pertussis toxin, suggesting that a pertussis toxin-sensitive G protein may link the insulin receptor to the H2O2-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 H2O2 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 H2O2 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 H2O2 signaling may lead to the development of cerebral insulin resistance.
References
- Hoppe Seylers Z Physiol Chem. 1972 Jun;353(6):987-99 - PubMed
- Arch Biochem Biophys. 2009 Aug 1;488(1):69-75 - PubMed
- J Biol Chem. 1988 Feb 25;263(6):2969-80 - PubMed
- J Biol Chem. 2012 Aug 3;287(32):27255-64 - PubMed
- Cell Signal. 2004 Mar;16(3):323-31 - PubMed
- J Neurosci. 2000 Dec 15;20(24):8972-9 - PubMed
- J Biol Chem. 1997 Apr 11;272(15):10135-43 - PubMed
- J Mol Med (Berl). 1997 Apr;75(4):283-9 - PubMed
- J Biol Chem. 1995 Apr 7;270(14):8122-30 - PubMed
- J Neurosci. 1999 Sep 1;19(17):7300-8 - PubMed
- Neural Dev. 2010 Mar 15;5:7 - PubMed
- Biochem Biophys Res Commun. 1971 Aug 6;44(3):526-32 - PubMed
- J Neural Transm Suppl. 2001;(61):223-35 - PubMed
- Mol Cell Biol. 2004 Mar;24(5):1844-54 - PubMed
- J Biol Chem. 1975 Sep 25;250(18):7114-9 - PubMed
- J Neurochem. 2002 Mar;80(5):780-7 - PubMed
- FEBS Lett. 1971 Sep 15;17(1):11-13 - PubMed
- J Biol Chem. 2007 Oct 19;282(42):30523-34 - PubMed
- Proc Natl Acad Sci U S A. 2004 Jun 15;101(24):8852-7 - PubMed
- Endocrinology. 1991 Oct;129(4):2058-66 - PubMed
- J Mol Neurosci. 1998 Oct;11(2):151-64 - PubMed
- J Biol Chem. 1979 Apr 10;254(7):2214-20 - PubMed
- Bull Exp Biol Med. 2002 Jun;133(6):568-70 - PubMed
- Biochemistry. 1971 Dec 7;10(25):4763-70 - PubMed
- Diabetes. 2005 Feb;54(2):311-21 - PubMed
- J Biol Chem. 2007 Apr 20;282(16):11885-92 - PubMed
- FEBS Lett. 2000 Jun 16;475(2):121-6 - PubMed
- J Biol Chem. 2004 Feb 6;279(6):4127-35 - PubMed
- Nature. 1996 Feb 29;379(6568):840-4 - PubMed
- J Biol Chem. 2001 Jun 15;276(24):21938-42 - PubMed
- Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H758-66 - PubMed
- J Biol Chem. 2001 Dec 28;276(52):48662-9 - PubMed
- J Neurochem. 1990 May;54(5):1661-5 - PubMed
- Brain Res. 2003 Mar 28;967(1-2):152-60 - PubMed
- Brain Res. 2004 Mar 12;1000(1-2):32-9 - PubMed
- J Clin Invest. 2012 Apr;122(4):1316-38 - PubMed
- FEBS Lett. 1997 Oct 13;416(1):15-8 - PubMed
- FEBS Lett. 1972 Apr 15;22(1):57-60 - PubMed
- Neurosci Lett. 2001 Apr 20;302(2-3):141-5 - PubMed
- Trends Biochem Sci. 1996 Dec;21(12):460-6 - PubMed
- Biochem Biophys Res Commun. 1971 Mar 19;42(6):1016-23 - PubMed
- J Biol Chem. 2001 Jun 29;276(26):23357-61 - PubMed
- Biol Res. 2006;39(1):7-13 - PubMed
- J Biol Chem. 2001 Oct 26;276(43):39705-12 - PubMed
- J Alzheimers Dis. 2007 May;11(2):153-64 - PubMed
- Proc Natl Acad Sci U S A. 1981 Nov;78(11):6840-4 - PubMed
- Biochem J. 2009 Jan 1;417(1):1-13 - PubMed
- J Biol Chem. 1994 Aug 19;269(33):21037-42 - PubMed
- J Biol Chem. 2001 Sep 14;276(37):34651-8 - PubMed
- Curr Drug Metab. 2008 Oct;9(8):686-96 - PubMed
- Science. 1994 Jan 7;263(5143):95-8 - PubMed
- Proc Natl Acad Sci U S A. 1983 Jun;80(11):3237-40 - PubMed
- Biochem Pharmacol. 1978;27(22):2589-94 - PubMed
- FASEB J. 1999 Sep;13(12):1491-500 - PubMed
- J Biol Chem. 1994 Jan 7;269(1):1-4 - PubMed
- Cell Metab. 2009 Oct;10(4):260-72 - PubMed
- Biochem J. 1973 Jul;134(3):707-16 - PubMed
- Biochem J. 2009 Dec 23;425(2):313-25 - PubMed
- FASEB J. 1998 Jul;12(10):863-70 - PubMed
- J Neurochem. 2004 Jul;90(2):405-21 - PubMed
- Cell. 2004 Dec 17;119(6):873-87 - PubMed
- J Aging Res. 2012;2012:384017 - PubMed
- Pflugers Arch. 2000 Oct;440(6):941-7 - PubMed
- BMC Neurosci. 2007 Oct 08;8:84 - PubMed
- FEBS Lett. 1996 Nov 18;397(2-3):230-4 - PubMed
- Neuroscience. 2004;127(4):833-43 - PubMed
- J Biol Chem. 1948 Dec;176(3):1085-94 - PubMed
- Biochimie. 1985 Oct-Nov;67(10-11):1147-53 - PubMed
- BMC Cell Biol. 2002 May 31;3:12 - PubMed
- Biochem J. 2004 Jun 15;380(Pt 3):831-6 - PubMed
- J Neurochem. 2001 Oct;79(2):266-77 - PubMed
- Annu Rev Biochem. 1995;64:97-112 - PubMed
- Biochem Biophys Res Commun. 1998 Dec 18;253(2):295-9 - PubMed
- Brain Res. 1991 May 10;548(1-2):322-5 - PubMed
- J Neurochem. 1986 Sep;47(3):831-6 - PubMed
Publication Types