Single transmembrane domain insulin-like growth factor-II receptor and G protein: potential interaction and its significance in brain function

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The insulin-like growth factor-II (IGF-II) receptor is a single transmembrane glycoprotein containing a large extracellular domain and small cytoplasmic tail. The receptor interacts with the IGF-II and mannose 6-phosphate-bearing lysosomal enzymes via two distinct sites. A majority of the receptors are expressed within trans-Golgi network/endosomal compartments, where they divert newly synthesized lysosomal enzymes from the secretory pathway to endosomes and lysosomes. A subset of receptors located on the plasma membrane regulates endocytosis of secreted lysosomal enzymes, mediates internalization and degradation of IGF-II. Unlike intracellular trafficking, the role of the IGF-II receptor in the transmembrane signaling of IGF-II remains poorly understood. We have recently reported that the IGF-II receptor of the brain is coupled to a G protein and its activation by IGF-II or Leu27IGF-II, an analog that binds preferentially to the IGF-II receptor, potentiates acetylcholine release but decrease GABA release from the rat hippocampus by a G protein-sensitive pathway. Additionally, we observed that IGF-II receptors are associated with G protein-coupled receptor interacting protein beta-arrestin-2 and are translocated from detergent-resistant membrane to detergent-soluble membrane fractions following stimulation with agonist. These results led us to hypothesize that the single transmembrane domain IGF-II receptor in the brain is coupled to a G-protein and its activation can mediate specific biological responses by triggering G protein-linked intracellular signaling mechanism. To address this issue we propose i) to establish the specificity of the IGF-II receptor interaction with G protein/beta-arrestin-2, ii) to evaluate whether the IGF-II receptor interacts directly or indirectly with the G protein, iii) to determine the mechanisms by which IGF-II attenuates hippocampal GABA release and iv) to study alterations in the GABAergic and cholinergic systems in the brain of IGF-II receptor overexpressing transgenic mice. We believe that this study should not only provide evidence for the physiological relevance of IGF-II receptor in normal brain but it will also pave the way for a better understanding of its role in neurodegenerative diseases.