SIGNIFICANCE OF THE MULTIFUNCTIONAL INSULIN-LIKE GROWTH FACTOR-II RECEPTOR IN REGULATING NORMAL BRAIN FUNCTION

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The insulin-like growth factor-II (IGF-II) receptor is a single-pass multifunctional glycoprotein containing a large extracellular domain and a small cytoplasmic tail. The receptor interacts with IGF-II and mannose 6-phosphate (M6P)-bearing ligands, such as lysosomal enzymes via two distinct sites. Majority of the receptors are expressed within trans-Golgi/endosomal compartments and are involved in the segregation of newly synthesized lysosomal enzymes for sorting to endosomes/lysosomes. A subset of receptors located on the plasma membrane regulates internalization of IGF-II and M6P-containing ligands for their clearance or activation. Receptor dimerization has been suggested to play a role in optimal binding and internalization of M6P-bearing ligands. There is also evidence that the IGF-II receptor participates in mediating certain biological actions of IGF-II by activating specific intracellular signaling pathways. At present, while the trafficking role of the receptor is well established, its significance in transmembrane signaling in response to IGF-II binding remains controversial. Using a variety of approaches, we have reported that i) the single-pass IGF-II receptor is coupled to a G-protein and its activation by Leu27IGF-II, an IGF-II analog that binds preferentially to the receptor, potentiates acetylcholine release but attenuates GABA release from adult rat hippocampus by a pertussis toxin (PTX)-sensitive pathway and ii) activation of the receptor leads to its translocation from detergent-resistant to detergent-soluble membrane fractions and stimulation of extracellular signal-related kinase 1/2 via a PTX-dependent pathway. Our recent preliminary data further indicate that i) binding of [125I]IGF-II but not the M6P ligand [125I]PMB-BSA to the IGF-II receptor is inhibited by GTP analogue GTPγS, ii) PTX treatment attenuates internalization of [125I]IGF-II in hippocampal cultured neurons, iii) Leu27IGF-II potentiates hippocampal glutamate release and enhances spatial learning in adult arts. Thus, we hypothesize that single transmembrane domain IGF-II receptor, by interaction with a G-protein, can directly regulate biological functions of IGF-II in the adult rat brain. To address this issue we propose: i) to determine whether IGF-II receptor-mediated G-protein signaling can occur in the presence of M6P-ligands, ii) to establish if dimerization of the IGF-II receptor is necessary for its signaling effects, iii) to determine the fate of the IGF-II receptor following induction of G-protein-mediated signaling cascade and iv) to establish the role of glutamate and acetylcholine in IGF-II-mediated enhancement of cognitive function. We believe that this study should generate original data regarding specificity of interactions between the IGF-II receptor and G protein and help to define its significance in regulating normal brain functions.