Review
Receptors for acylethanolamides—GPR55 and GPR119

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Abstract

Acylethanolamides are lipid substances widely distributed in the body, generated from a membrane phospholipid precursor, N-acylphosphatidylethanolamine (NAPE). The recent identification of arachidonoyl ethanolamide (anandamide or AEA) as an endogenous cannabinoid ligand has focused attention on acylethanolamides, which has further increased with the subsequent identification of related additional acylethanolamides with signaling function, such as oleoylethanolamide (OEA) and palmitoylethanolamide (PEA). Most of the biological functions of anandamide are mediated by the two G protein-coupled cannabinoid receptors identified to date, CB1 and CB2, with the transient receptor potential vanilloid-1 receptor being an additional potential target. There has been increasing pharmacological evidence for the existence of additional cannabinoid receptors, with the orphan G protein-coupled receptor GPR55 being the most actively scrutinized, and is one of the subjects of this review. The other receptor reviewed here is GPR119, which can recognize OEA and PEA. These two acylethanolamides, although structurally related to anandamide, do not interact with classical cannabinoid receptors. Instead, they have high affinity for the nuclear receptor PPARα, which is believed to mediate many of their biological effects.

Section snippets

Acylethanolamides

Acylethanolamides or fatty acid ethanolamides are lipid substances widely distributed in the body, present both in brain and various peripheral tissues, most notably in the gastrointestinal tract [1]. They are thought to be generated from a membrane phospholipid precursor, N-acylphosphatidylethanolamine (NAPE) by phospholipase d-mediated cleavage [2], although additional, parallel enzymatic pathways have also been identified [3], [4]. NAPE has been recently identified as a hormone-like anorexic

The structure of GPR55

The cloning of the human GPR55 was originally reported in 1999, when it was described as a classical intronless GPCR that maps to chromosome 2 and consists of 319 amino acids. Philogenetically, GPR55 belongs to the δ (purine) cluster of the rhodopsin family that comprises receptors for adenosine and uridine nucleotides and also contains some orphan receptors [25], [26]. It displays limited amino acid sequence homology with GPR23 (30%), P2Y5 (29%), GPR35 (27%) and CCR4 (23%), homologies with CB1

Structure of GPR119

The human orphan receptor GPR119 was identified through a bioinformatics approach [26]. Its sequence was found to align with the earlier reported hGPCR2 receptor [59] and it is present in other mammalian species [26], [60]. The 335 amino acid hGPR119 protein is encoded by an intronless gene located on chromosome X [26], [59]. Philogenetically, GPR119 has been assigned to the MECA (melanocortin; endothelial differentiation gene; cannabinoid; adenosine) receptor cluster, which designates

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    Current address: Keufbeuren Hospital, Keufbeuren, Germany.

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