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Hawkes, Cheryl; Jhamandas, Jack H.; Harris, Kim H.; Fu, Wen; MacDonald, Richard G. and Kar, Satyabrata
(2006).
DOI: https://doi.org/10.1523/JNEUROSCI.2730-05.2006
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.
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About
- Item ORO ID
- 44109
- Item Type
- Journal Item
- ISSN
- 1529-2401
- Keywords
- cholinergic neurons; G-protein-coupled receptor; insulin-like growth factors; intracellular signaling; neurotransmitter release; protein kinase C
- Academic Unit or School
-
Faculty of Science, Technology, Engineering and Mathematics (STEM) > Life, Health and Chemical Sciences
Faculty of Science, Technology, Engineering and Mathematics (STEM) - Copyright Holders
- © 2006 Society for Neuroscience
- Depositing User
- Cheryl Hawkes