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Involvement of dopamine receptors and β‐arrestin in metamphetamine‐induced inclusions formation in pc12 cells
Author(s) -
Fornai Francesco,
Lenzi Paola,
Capobianco Loredana,
Iacovelli Luisa,
Scarselli Pamela,
Lazzeri Gloria,
De Blasi Antonio
Publication year - 2008
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2008.05284.x
Subject(s) - intracellular , arrestin , microbiology and biotechnology , ubiquitin , dopamine , receptor , proteasome , dopamine receptor , chemistry , biology , signal transduction , biochemistry , g protein coupled receptor , endocrinology , gene
Abstract Exposure of PC12 cells to metamphetamine (MA) induces the formation of multilamellar structures (whorls) resembling autophagic granules that subsequently develop as intracellular inclusions. These inclusions stain for a variety of antigens belonging to the ubiquitin proteasome pathway. Since MA‐induced intracellular bodies require the presence of dopamine in the present study we analyzed the role of dopamine (DA) receptors in producing neuronal inclusions. Moreover, we investigated potential signaling pathways which could lead to ubiquitination in the presence of MA. Based on recent reports that ubiquitination of β‐adrenergic receptors is promoted by β‐arrestin which shuttles proteins from the plasma membrane to the ubiquitin proteasome system we investigated whether β‐arrestin is involved in MA‐induced inclusion formation. Our experiments document that (i) β‐arrestin was associated with MA‐induced intracellular bodies; (ii) MA induced a rapid and reversible ubiquitination of β‐arrestin; (iii) dopamine antagonists reduced both MA‐induced β‐arrestin ubiquitination and intracellular whorls formation; (iv) the number of MA‐induced intracellular bodies was reduced in cells transfected with the β‐arrestin dominant negative mutant, βarrV53D and was increased by the persistently ubiquitinated β‐arrestin‐ubiquitin fusion protein. In conclusion, the present study demonstrates the involvement of β‐arrestin in MA‐induced intracellular bodies and the participation of dopamine receptors in this process.