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Title: GPR55 and N-acyl amino acids
Author: Penman, June
Awarding Body: University of Dundee
Current Institution: University of Dundee
Date of Award: 2013
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G-protein coupled receptor 55 (GPR55) is a novel lipid sensing receptor activated by the endogenous lipid, lysophosphatidylinositol (LPI) and is reported as a putative cannabinoid receptor. However GPR55 shares limited homology with the two cloned cannabinoid receptors (CB1 and CB2) but does exhibit some cannabinoid sensitivity. Recently a family of bioactive lipids, the N-acyl amino acids, are gaining interest due to their structural similarity to endocannabinoids (naturally occurring CB1 and CB2 agonists). N-acyl amino acids have little or no affinity for either CB1 or CB2 and many have no known biological target at present. This study used a subset of N-acyl amino acids; possessing either a serine or glycine head group attached to varying fatty acid chains; to assess these novel lipids as potential GPR55 ligands. Three cell lines were utilised, a stably transfected HEK293 cell line that overexpresses 3xHA N-terminus tagged hGPR55 (hGPR55-HEK293 cells) and control HEK293 cells. In addition, the DU145 a prostate cancer cell line which is reported to endogenously express GPR55 was investigated. N-acyl amino acid challenge activated GPR55 to promote Ca2+ mobilisation, CREB phosphorylation, actin cytoskeletal reorganisation and elongation of focal adhesions. Furthermore GPR55-mediated downstream signalling effectors were studied comparing LPI to the orphan lipid; N oleoyl-L-serine (NOSer). This study highlights that N-acyl amino acids act as GPR55 agonist/partial agonists in hGPR55-HEK293 cells. Both LPI and NOSer exert effects in prostate cancer cells (DU145s) which are GPR55 mediated. GPR55 may exhibit ligand bias as LPI was more efficacious in Ca2+ mobilisation. However in the pCREB assay NOSer was more efficacious than LPI. A similar efficacy and potency to either LPI or NOSer was observed in the other assays in both hGPR55-HEK293 and DU145 cells. Furthermore this study is the first where a named GPCR can be assigned for responses that are mediated by NOSer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available