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Link to original content: http://pubmed.ncbi.nlm.nih.gov/29390908/
Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12 - PubMed Skip to main page content
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Review
. 2018 Feb;50(1):74-93.
doi: 10.1080/03602532.2018.1428616. Epub 2018 Feb 1.

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Paula Morales  1 , Israa Isawi  1 , Patricia H Reggio  1
Affiliations
Review

Towards a better understanding of the cannabinoid-related orphan receptors GPR3, GPR6, and GPR12

Paula Morales et al. Drug Metab Rev. 2018 Feb.

Abstract

GPR3, GPR6, and GPR12 are three orphan receptors that belong to the Class A family of G-protein-coupled receptors (GPCRs). These GPCRs share over 60% of sequence similarity among them. Because of their close phylogenetic relationship, GPR3, GPR6, and GPR12 share a high percentage of homology with other lipid receptors such as the lysophospholipid and the cannabinoid receptors. On the basis of sequence similarities at key structural motifs, these orphan receptors have been related to the cannabinoid family. However, further experimental data are required to confirm this association. GPR3, GPR6, and GPR12 are predominantly expressed in mammalian brain. Their high constitutive activation of adenylyl cyclase triggers increases in cAMP levels similar in amplitude to fully activated GPCRs. This feature defines their physiological role under certain pathological conditions. In this review, we aim to summarize the knowledge attained so far on the understanding of these receptors. Expression patterns, pharmacology, physiopathological relevance, and molecules targeting GPR3, GPR6, and GPR12 will be analyzed herein. Interestingly, certain cannabinoid ligands have been reported to modulate these orphan receptors. The current debate about sphingolipids as putative endogenous ligands will also be addressed. A special focus will be on their potential role in the brain, particularly under neurological conditions such as Parkinson or Alzheimer's disease. Reported physiological roles outside the central nervous system will also be covered. This critical overview may contribute to a further comprehension of the physiopathological role of these orphan GPCRs, hopefully attracting more research towards a future therapeutic exploitation of these promising targets.

Keywords: GPR12; GPR3; GPR6; Orphan receptors; cannabinoids; neurodegenerative diseases.

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Conflict of interest statement

Declaration of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Phylogenetic tree representation of the MECA cluster. The orphan subset GPR3/6/12 is highlighted using the following color-coding: GPR3 in red; GPR6 in green; GPR12 in blue.
Figure 2
Figure 2
Schematic representation of GPR3, GPR6 and GPR12 expression. A) Peripheral expression; B) Expression in the CNS. Color coding: GPR3 in red, GPR6 in green, GPR12 in blue; darker colors represent higher expression whereas lighter ones refer to lower expression. White circles refer to very low or no receptor expression.
Figure 3
Figure 3
Structure of putative endogenous GPR3/6/12 ligands.
Figure 4
Figure 4
Structure of the GPR3 agonist DPI.
Figure 5
Figure 5
Structure of the first triazolopyrimidine identified as a GPR3 inverse agonist, compound 1, and its optimized analog AF64394.
Figure 6
Figure 6
Structure of CBD and its related analogs CBDV and CBDD.
Figure 7
Figure 7
Structures of the selected pyridazine analogs that modulate GPR6.
Figure 8
Figure 8
Structures of imidazolidinethiones ARE111 and ARE133, and imidazodithiazoles ARE112 and ARE136.
Figure 9
Figure 9
Structure of the GPR12 modulator tyrosol.
See this image and copyright information in PMC

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