Cannabinoid receptor trafficking in peripheral cells is dynamically regulated by a binary biochemical switch

Kleyer, Jonas; Nicolussi, Simon; Taylor, Peter; Simonelli, Deborah; Furger, Evelyne; Anderle, Pascale; Gertsch, Jürg (2012). Cannabinoid receptor trafficking in peripheral cells is dynamically regulated by a binary biochemical switch. Biochemical pharmacology, 83(10), pp. 1393-412. New York, N.Y.: Elsevier 10.1016/j.bcp.2012.02.014

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The cannabinoid G protein-coupled receptors (GPCRs) CB₁ and CB₂ are expressed in different peripheral cells. Localization of GPCRs in the cell membrane determines signaling via G protein pathways. Here we show that unlike in transfected cells, CB receptors in cell lines and primary human cells are not internalized upon agonist interaction, but move between cytoplasm and cell membranes by ligand-independent trafficking mechanisms. Even though CB receptors are expressed in many cells of peripheral origin they are not always localized in the cell membrane and in most cancer cell lines the ratios between CB₁ and CB₂ receptor gene and surface expression vary significantly. In contrast, CB receptor cell surface expression in HL60 cells is subject to significant oscillations and CB₂ receptors form oligomers and heterodimers with CB₁ receptors, showing synchronized surface expression, localization and trafficking. We show that hydrogen peroxide and other nonspecific protein tyrosine phosphatase inhibitors (TPIs) such as phenylarsine oxide trigger both CB₂ receptor internalization and externalization, depending on receptor localization. Phorbol ester-mediated internalization of CB receptors can be inhibited via this switch. In primary human immune cells hydrogen peroxide and other TPIs lead to a robust internalization of CB receptors in monocytes and an externalization in T cells. This study describes, for the first time, the dynamic nature of CB receptor trafficking in the context of a biochemical switch, which may have implications for studies on the cell-type specific effects of cannabinoids and our understanding of the regulation of CB receptor cell surface expression.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Biochemistry and Molecular Medicine

UniBE Contributor:

Kleyer, Jonas; Nicolussi, Simon; Anderle, Pascale and Gertsch, Jürg

ISSN:

0006-2952

Publisher:

Elsevier

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:37

Last Modified:

06 Dec 2013 13:37

Publisher DOI:

10.1016/j.bcp.2012.02.014

PubMed ID:

22387618

Web of Science ID:

000302435000009

URI:

https://boris.unibe.ch/id/eprint/15031 (FactScience: 222185)

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