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Regulated endosomal trafficking of Diacylglycerol lipase alpha (DAGLα) generates distinct cellular pools; implications for endocannabinoid signaling.

Mol. Cell. Neurosci.2016 Oct;76:76-86. Epub 2016 Sep 03
Ya Zhou 1 , Fiona V Howell 1 , Oleg O Glebov 1 , David Albrecht 2 , Gareth Williams 1 , Patrick Doherty 3
Ya Zhou 1 , Fiona V Howell 1 , Oleg O Glebov 1 , David Albrecht 2 , Gareth Williams 1 , Patrick Doherty 3
+ et al

[No authors listed]

Author information
  • 1 Wolfson Centre for Age-Related Diseases, King's College London, SE1 1UL, UK.
  • 2 Randall Division of Cell and Molecular Biophysics, King's College London, SE1 1UL, UK.
  • 3 Wolfson Centre for Age-Related Diseases, King's College London, SE1 1UL, UK. Electronic address: patrick.doherty@kcl.ac.uk.

摘要


Diacylglycerol lipase alpha (DAGLα) generates the endocannabinoid (eCB) 2-arachidonylglycerol (2-AG) that regulates the proliferation and differentiation of neural stem cells and serves as a retrograde signaling lipid at synapses. Nothing is known about the dynamics of DAGLα expression in cells and this is important as it will govern where 2-AG can be made and released. We have developed a new construct to label DAGLα at the surface of live cells and follow its trafficking. In hippocampal neurons a cell surface pool of DAGLα co-localizes with Homer, a postsynaptic density marker. This surface pool of DAGLα is dynamic, undergoing endocytosis and recycling back to the postsynaptic membrane. A similar cycling is seen in COS-7 cells with the internalized DAGLα initially transported to EEA1 and Rab5-positive early endosomes via a clathrin-independent pathway before being transported back to the cell surface. The internalized DAGLα is present on reticular structures that co-localize with microtubules. Importantly, DAGLα cycling is a regulated process as inhibiting results in a significant reduction in endocytosis. This is the first description of DAGLα cycling between the cell surface and an intracellular endosomal compartment in a manner that can regulate the level of the enzyme at the cell surface.

KEYWORDS: 2-AG, DAGLα, Endocannabinoid, Endocytosis, Endosomes, Trafficking