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Calpain hydrolysis of alpha- and beta2-adaptins decreases clathrin-dependent endocytosis and may promote neurodegeneration.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2009 May 01; Vol. 284 (18), pp. 12447-58. Date of Electronic Publication: 2009 Feb 24. - Publication Year :
- 2009
-
Abstract
- Clathrin-dependent endocytosis is mediated by a tightly regulated network of molecular interactions that provides essential protein-protein and protein-lipid binding activities. Here we report the hydrolysis of the alpha- and beta2-subunits of the tetrameric adaptor protein complex 2 by calpain. Calcium-dependent alpha- and beta2-adaptin hydrolysis was observed in several rat tissues, including brain and primary neuronal cultures. Neuronal alpha- and beta2-adaptin cleavage was inducible by glutamate stimulation and was accompanied by the decreased endocytosis of transferrin. Heterologous expression of truncated forms of the beta2-adaptin subunit significantly decreased the membrane recruitment of clathrin and inhibited clathrin-mediated receptor endocytosis. Moreover, the presence of truncated beta2-adaptin sensitized neurons to glutamate receptor-mediated excitotoxicity. Proteolysis of alpha- and beta2-adaptins, as well as the accessory clathrin adaptors epsin 1, adaptor protein 180, and the clathrin assembly lymphoid myeloid leukemia protein, was detected in brain tissues after experimentally induced ischemia and in cases of human Alzheimer disease. The present study further clarifies the central role of calpain in regulating clathrin-dependent endocytosis and provides evidence for a novel mechanism through which calpain activation may promote neurodegeneration: the sensitization of cells to glutamate-mediated excitotoxicity via the decreased internalization of surface receptors.
- Subjects :
- Adaptor Protein Complex alpha Subunits genetics
Adaptor Protein Complex beta Subunits genetics
Adaptor Proteins, Vesicular Transport
Alzheimer Disease genetics
Alzheimer Disease pathology
Animals
Brain pathology
Brain Ischemia genetics
Brain Ischemia metabolism
Brain Ischemia pathology
Calcium metabolism
Calpain genetics
Cell Line
Cell Membrane genetics
Cell Membrane metabolism
Cell Membrane pathology
Clathrin genetics
Female
Glutamic Acid metabolism
Humans
Hydrolysis
Male
Membrane Lipids genetics
Membrane Lipids metabolism
Monomeric Clathrin Assembly Proteins genetics
Monomeric Clathrin Assembly Proteins metabolism
Neurons pathology
Rats
Rats, Sprague-Dawley
Rats, Wistar
Adaptor Protein Complex alpha Subunits metabolism
Adaptor Protein Complex beta Subunits metabolism
Alzheimer Disease metabolism
Brain metabolism
Calpain metabolism
Clathrin metabolism
Endocytosis
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 284
- Issue :
- 18
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 19240038
- Full Text :
- https://doi.org/10.1074/jbc.M804740200