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TDP‐43 interacts with cannabinoid type 1 receptor modulating its subcellular localization and function
Author(s) -
Filipeanu Catalin,
Deshotels Matthew,
Weed Peter,
Ogunlade Blessing,
Robinson Anastasia G,
Winsauer Peter,
Guidry Jessie J.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.1266.3
Subject(s) - hek 293 cells , receptor , transfection , microbiology and biotechnology , immunoprecipitation , ubiquitin , frontotemporal lobar degeneration , chemistry , biology , biochemistry , medicine , gene , frontotemporal dementia , dementia , disease
To identify new molecular chaperones of cannabinoid type 1 receptor (CB1R) we used a proteomic approach in HEK293T cells, transfected with two spicing variants of this receptor, CB1R and CB1AR. These two isoforms differ only in the composition of the N‐terminus domain. Surprisingly, the only protein found to interact differently with CB1R and CB1AR was transactive response DNA‐Binding Protein 43 (TDP‐43), which is known to be involved in the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). The specific interactions between CB1R and TDP‐43 were also confirmed by co‐immunoprecipitation not only in transfected HEK293 cells, but also at the endogenous level in rat crude spinal cord. TDP‐43 overexpression decreased CB1R plasma membrane levels by stimulating receptor internalization, but it did not change the total receptor levels. Further, TDP‐43 enhanced CB1R ubiquitination to similar levels, as induced by the full CB1R agonist, CP55940. Also, overexpression of TDP‐43 resulted in reduced effects of CB1R effects on cAMP, P‐ERK1/2, and P‐CREB responses. Present results revealed TDP‐43 as an unexpected molecular chaperone of CB1R and these findings may have significance not only in the regulation of CB1R intracellular trafficking, but also in the treatment of ALS and FTLD. Support or Funding Information This work was supported by Startup Funds from Howard University (CF) and USPHS grant DA019625 (PW) from the National Institute on Drug Abuse