Heterotrimeric G Proteins and the Single-Transmembrane Domain IGF-II/M6P Receptor: Functional Interaction and Relevance to Cell Signaling |
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Authors: | C Hawkes A Amritraj R G MacDonald J H Jhamandas S Kar |
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Institution: | (1) Department of Psychiatry, Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, AB, Canada, T6G 2B7;(2) Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA;(3) Department of Medicine (Neurology), Centre for Alzheimer and Neurodegenerative Research, University of Alberta, Edmonton, AB, Canada, T6G 2B7;(4) Alberta Centre for Prions and Protein Folding Diseases Departments of Medicine (Neurology) and Psychiatry, University of Alberta, Edmonton, AB, Canada, T6G 2M8 |
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Abstract: | The G protein-coupled receptor (GPCR) family represents the largest and most versatile group of cell surface receptors. Classical
GPCR signaling constitutes ligand binding to a seven-transmembrane domain receptor, receptor interaction with a heterotrimeric
G protein, and the subsequent activation or inhibition of downstream intracellular effectors to mediate a cellular response.
However, recent reports on direct, receptor-independent G protein activation, G protein-independent signaling by GPCRs, and
signaling of nonheptahelical receptors via trimeric G proteins have highlighted the intrinsic complexities of G protein signaling
mechanisms. The insulin-like growth factor-II/mannose-6 phosphate (IGF-II/M6P) receptor is a single-transmembrane glycoprotein
whose principal function is the intracellular transport of lysosomal enzymes. In addition, the receptor also mediates some
biological effects in response to IGF-II binding in both neuronal and nonneuronal systems. Multidisciplinary efforts to elucidate
the intracellular signaling pathways that underlie these effects have generated data to suggest that the IGF-II/M6P receptor
might mediate transmembrane signaling via a G protein-coupled mechanism. The purpose of this review is to outline the characteristics
of traditional and nontraditional GPCRs, to relate the IGF-II/M6P receptor’s structure with its role in G protein-coupled
signaling and to summarize evidence gathered over the years regarding the putative signaling of the IGF-II/M6P receptor mediated
by a G protein. |
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Keywords: | G protein-coupled receptor IGF-II/MGP Heterotrimeric G protein |
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