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The Journal of Neuroscience, January 11, 2006, 26(2):585-596; doi:10.1523/JNEUROSCI.2730-05.2006
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Cellular/Molecular
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
Cheryl Hawkes,1,2
Jack H. Jhamandas,3
Kim H. Harris,3
Wen Fu,3
Richard G. MacDonald,4 and
Satyabrata Kar1,2,3
1Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec, Canada H3A 2B4, Departments of 2Psychiatry and 3Medicine (Neurology), Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, Alberta, Canada T6G 2B7, and 4Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198
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 C (PKC)-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.
Key words: cholinergic neurons; G-protein-coupled receptor; intracellular signaling; insulin-like growth factors; neurotransmitter release; protein kinase C
Received June 30, 2004;
revised November 21, 2005;
accepted November 23, 2005.
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