PT - JOURNAL ARTICLE AU - Cheryl Hawkes AU - Jack H. Jhamandas AU - Kim H. Harris AU - Wen Fu AU - Richard G. MacDonald AU - Satyabrata Kar TI - 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 AID - 10.1523/JNEUROSCI.2730-05.2006 DP - 2006 Jan 11 TA - The Journal of Neuroscience PG - 585--596 VI - 26 IP - 2 4099 - http://www.jneurosci.org/content/26/2/585.short 4100 - http://www.jneurosci.org/content/26/2/585.full SO - J. Neurosci.2006 Jan 11; 26 AB - 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.