Multiple Topological Domains Mediate Subtype-specific Internalization of the M2 Muscarinic Acetylcholine Receptor
| Autor: | Michael L. Schlador, Robert D. Grubbs, Neil M. Nathanson |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Dynamins
health care facilities manpower and services media_common.quotation_subject Molecular Sequence Data education Down-Regulation Biology Transfection Endocytosis Biochemistry GTP Phosphohydrolases Epitopes Muscarinic acetylcholine receptor Muscarinic acetylcholine receptor M5 Tumor Cells Cultured Animals Humans Amino Acid Sequence Receptor Internalization Molecular Biology health care economics and organizations Dynamin G protein-coupled receptor media_common Receptor Muscarinic M2 Sequence Homology Amino Acid Cell Biology Receptors Muscarinic Cell biology COS Cells Signal transduction |
| Zdroj: | Journal of Biological Chemistry. 275:23295-23302 |
| ISSN: | 0021-9258 |
| DOI: | 10.1074/jbc.m002380200 |
| Popis: | Endocytosis of agonist-activated G protein-coupled receptors (GPCRs) is required for both resensitization and recycling to the cell surface as well as lysosomal degradation. Thus, this process is crucial for regulation of receptor signaling and cellular responsiveness. Although many GPCRs internalize into clathrin-coated vesicles in a dynamin-dependent manner, some receptors, including the M(2) muscarinic acetylcholine receptor (mAChR), can also exhibit dynamin-independent internalization. We have identified five amino acids, located in the sixth and seventh transmembrane domains and the third intracellular loop, that are essential for agonist-induced M(2) mAChR internalization via a dynamin-independent mechanism in JEG-3 choriocarcinoma cells. Substitution of these residues into the M(1) mAChR, which does not internalize in these cells, is sufficient for conversion to the internalization-competent M(2) mAChR phenotype, whereas removal of these residues from the M(2) mAChR blocks internalization. Cotransfection of a dominant-negative isoform of dynamin has no effect on M(2) mAChR internalization. An internalization-incompetent M(2) mutant that lacks a subset of the necessary residues can still internalize via a G protein-coupled receptor kinase-2 and beta-arrestin-dependent pathway. Furthermore, internalization is independent of the signal transduction pathway that is activated. These results identify a novel motif that specifies structural requirements for subtype-specific dynamin-independent internalization of a GPCR. |
| Databáze: | OpenAIRE |
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