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Single transmembrane domain insulin-like growth factor-II/mannose-6- phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway

Hawkes, Cheryl; Jhamandas, Jack H.; Harris, Kim H.; Fu, Wen; MacDonald, Richard G. and Kar, Satyabrata (2006). Single transmembrane domain insulin-like growth factor-II/mannose-6- phosphate receptor regulates central cholinergic function by activating a G-protein-sensitive, protein kinase C-dependent pathway. Journal of Neuroscience, 26(2) pp. 585–596.

DOI (Digital Object Identifier) Link: https://doi.org/10.1523/JNEUROSCI.2730-05.2006
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Abstract

The insulin-like growth factor-II/mannose-6-phosphate (IGF-II/M6P) receptor is a single-pass transmembrane glycoprotein that plays an important role in the intracellular trafficking of lysosomal enzymes and endocytosis-mediated degradation of IGF-II. However, its role in signal transduction after IGF-II binding remains unclear. In the present study, we report that IGF-II/M6P receptor in the rat brain is coupled to a G-protein and that its activation by Leu27IGF-II, an analog that binds rather selectively to the IGF-II/M6P receptor, potentiates endogenous acetylcholine release from the rat hippocampal formation. This effect is mediated by a pertussis toxin (PTX)-sensitive GTP-binding protein and is dependent on protein kinase Cα(PKCα)-induced phosphorylation of downstream substrates, myristoylated alanine-rich C kinase substrate, and growth associated protein-43. Additionally, treatment with Leu27IGF-II causes a reduction in whole-cell currents and depolarization of cholinergic basal forebrain neurons. This effect, which is blocked by an antibody against the IGF-II/M6P receptor, is also sensitive to PTX and is mediated via activation of a PKC-dependent pathway. These results together revealed for the first time that the single transmembrane domain IGF-II/M6P receptor expressed in the brain is G-protein coupled and is involved in the regulation of central cholinergic function via the activation of specific intracellular signaling cascades.

Item Type: Journal Item
Copyright Holders: 2006 Society for Neuroscience
ISSN: 1529-2401
Keywords: cholinergic neurons; G-protein-coupled receptor; insulin-like growth factors; intracellular signaling; neurotransmitter release; protein kinase C
Academic Unit/School: Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM)
Item ID: 44109
Depositing User: Cheryl Hawkes
Date Deposited: 03 Sep 2015 09:57
Last Modified: 07 Dec 2018 10:34
URI: http://oro.open.ac.uk/id/eprint/44109
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