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The Journal of Neuroscience, December 12, 2007, 27(50):13813-13821; doi:10.1523/JNEUROSCI.2069-07.2007

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Cellular/Molecular
Regulation of the Inositol 1,4,5-Trisphosphate Receptor Type I by O-GlcNAc Glycosylation

Juliana Rengifo,¹ Craig J. Gibson,¹ Eva Winkler,¹ Thibault Collin,² and Barbara E. Ehrlich¹

¹Department of Pharmacology and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06520, and ²Laboratoire de Physiologie Cérébrale, Université Paris 5, 75006 Paris, France

Correspondence should be addressed to Barbara E. Ehrlich, Department of Pharmacology, 333 Cedar Street, Yale University, New Haven, CT 06520-8066. Email: barbara.ehrlich{at}yale.edu

The inositol 1,4,5-trisphosphate (InsP₃) receptor type I (InsP₃R-I) is the principle channel for intracellular calcium (Ca²⁺) release in many cell types, including central neurons. It is regulated by endogenous compounds like Ca²⁺ and ATP, by protein partners, and by posttranslational modification. We report that the InsP₃R-I is modified by O-linked glycosylation of serine or threonine residues with β-N-acetylglucosamine (O-GlcNAc). The level of O-GlcNAcylation can be altered in vitro by the addition of the enzymes which add [OGT (O-GlcNActransferase)] or remove (O-GlcNAcase) this sugar or by loading cells with UDP-GlcNAc. We monitored the effects of this modification on InsP₃R function at the single-channel level and on intracellular Ca²⁺ transients. Single-channel activity was monitored with InsP₃R incorporated into bilayers; Ca²⁺ signaling was monitored using cells loaded with a Ca²⁺-sensitive fluorophore. We found that channel activity was decreased by the addition of O-GlcNAc and that this decrease was reversed by removal of the sugar. Similarly, cells loaded with UDP-GlcNAc had an attenuated response to uncaging of InsP₃. These results show that O-GlcNAcylation is an important regulator of the InsP₃R-I and suggest a mechanism for neuronal dysfunction under conditions in which O-GlcNAc is high, such as diabetes or physiological stress.

Key words: calcium imaging; calcium-sensitive dye; β-N-acetylglucosamine; O-GlcNActransferase; O-GlcNAcase; cerebellum; interneurons; inositol 1,4,5-trisphosphate receptor

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Received May 6, 2007; revised Sept. 25, 2007; accepted Sept. 26, 2007.

Correspondence should be addressed to Barbara E. Ehrlich, Department of Pharmacology, 333 Cedar Street, Yale University, New Haven, CT 06520-8066. Email: barbara.ehrlich{at}yale.edu

This article has been cited by other articles:

				T. Collin, R. Franconville, B. E. Ehrlich, and I. Llano Activation of Metabotropic Glutamate Receptors Induces Periodic Burst Firing and Concomitant Cytosolic Ca2+ Oscillations in Cerebellar Interneurons J. Neurosci., July 22, 2009; 29(29): 9281 - 9291. [Abstract] [Full Text] [PDF]

				M. K. Tallent, N. Varghis, Y. Skorobogatko, L. Hernandez-Cuebas, K. Whelan, D. J. Vocadlo, and K. Vosseller In Vivo Modulation of O-GlcNAc Levels Regulates Hippocampal Synaptic Plasticity through Interplay with Phosphorylation J. Biol. Chem., January 2, 2009; 284(1): 174 - 181. [Abstract] [Full Text] [PDF]

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