Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways

A. Chakraborty; C. Latapy; J. Xu; S. H. Snyder; J. M. Beaulieu

doi:10.1038/mp.2013.21

Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways

A. Chakraborty, C. Latapy, J. Xu, S. H. Snyder, J. M. Beaulieu

School of Medicine

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

Abstract

Glycogen synthase kinase 3 (GSK3), a prominent enzyme in carbohydrate metabolism, also has a major role in brain function. It is physiologically regulated by the kinase Akt, which phosphorylates GSK3 to inhibit catalytic activity. Inositol hexakisphosphate-1 (IP6K1) generates the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP7), which physiologically inhibits Akt leading to enhanced GSK3 activity. We report that IP6K1 binds and stimulates GSK3 enzymatic activity in a non-catalytic fashion. Physiological relevance is evident in the inhibition of GSK3 activity in the brains of IP6K1-deleted mice. Behavioral alterations of IP6K1 knockout mice resemble those of GSK3 mutants. Accordingly, modulation of IP6K1-GSK3β interaction may exert beneficial effects in psychiatric disorders involving GSK3.

Original language	English (US)
Pages (from-to)	284-293
Number of pages	10
Journal	Molecular psychiatry
Volume	19
Issue number	3
DOIs	https://doi.org/10.1038/mp.2013.21
State	Published - Mar 2014

Keywords

Behavior
GSK3
IP6K1

ASJC Scopus subject areas

Psychiatry and Mental health
Cellular and Molecular Neuroscience
Molecular Biology

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10.1038/mp.2013.21

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title = "Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways",

abstract = "Glycogen synthase kinase 3 (GSK3), a prominent enzyme in carbohydrate metabolism, also has a major role in brain function. It is physiologically regulated by the kinase Akt, which phosphorylates GSK3 to inhibit catalytic activity. Inositol hexakisphosphate-1 (IP6K1) generates the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP7), which physiologically inhibits Akt leading to enhanced GSK3 activity. We report that IP6K1 binds and stimulates GSK3 enzymatic activity in a non-catalytic fashion. Physiological relevance is evident in the inhibition of GSK3 activity in the brains of IP6K1-deleted mice. Behavioral alterations of IP6K1 knockout mice resemble those of GSK3 mutants. Accordingly, modulation of IP6K1-GSK3β interaction may exert beneficial effects in psychiatric disorders involving GSK3.",

keywords = "Behavior, GSK3, IP6K1",

author = "A. Chakraborty and C. Latapy and J. Xu and Snyder, {S. H.} and Beaulieu, {J. M.}",

note = "Funding Information: We thank Lynda Hester for primary neuronal cultures; Masoumeh Saleh, Kathye Aub{\'e}e and Nathalie Bouchard for mouse colony maintenance; Adele Snowman and Akrita Bhatnagar for protein purification; Krishna Juluri for providing human IP6K1 bacterial expression constructs and James Barrow for kindly providing synthetic IP7 for assay. This work was supported by US Public Health Service Grants MH18501 and DA-000266 (to SHS) and a Canadian Institutes of Health Research (CIHR, to JMB). JMB holds a Canada Research Chair in Molecular Psychiatry and is NARSAD Vital Projects Fund investigator.",

year = "2014",

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AU - Xu, J.

AU - Snyder, S. H.

AU - Beaulieu, J. M.

N1 - Funding Information: We thank Lynda Hester for primary neuronal cultures; Masoumeh Saleh, Kathye Aubée and Nathalie Bouchard for mouse colony maintenance; Adele Snowman and Akrita Bhatnagar for protein purification; Krishna Juluri for providing human IP6K1 bacterial expression constructs and James Barrow for kindly providing synthetic IP7 for assay. This work was supported by US Public Health Service Grants MH18501 and DA-000266 (to SHS) and a Canadian Institutes of Health Research (CIHR, to JMB). JMB holds a Canada Research Chair in Molecular Psychiatry and is NARSAD Vital Projects Fund investigator.

PY - 2014/3

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N2 - Glycogen synthase kinase 3 (GSK3), a prominent enzyme in carbohydrate metabolism, also has a major role in brain function. It is physiologically regulated by the kinase Akt, which phosphorylates GSK3 to inhibit catalytic activity. Inositol hexakisphosphate-1 (IP6K1) generates the inositol pyrophosphate diphosphoinositol pentakisphosphate (IP7), which physiologically inhibits Akt leading to enhanced GSK3 activity. We report that IP6K1 binds and stimulates GSK3 enzymatic activity in a non-catalytic fashion. Physiological relevance is evident in the inhibition of GSK3 activity in the brains of IP6K1-deleted mice. Behavioral alterations of IP6K1 knockout mice resemble those of GSK3 mutants. Accordingly, modulation of IP6K1-GSK3β interaction may exert beneficial effects in psychiatric disorders involving GSK3.

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Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways

Abstract

Keywords

ASJC Scopus subject areas

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