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

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 is 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.

Peroxisome Proliferator-Activated Receptors as a Therapeutic Target in Asthma

“…The CB1 receptor has been found in the central and peripheral nervous system, lungs, kidneys, and liver; the CB2 receptor is expressed by immune and hematopoietic cells. Recent evidence points out that endocannabinoids interact with not only these receptors but also G protein-coupled receptor 55 (GPR55) and all PPAR isoforms [96,132,133]. For example, it has been shown that endocannabinoids can serve as double agonists of PPARγ and CB2 and neutralize chronic inflammation [95].…”

“…Endocannabinoid receptors, like PPARs, are expressed by alveolar macrophages, eosinophils, monocytes, and dendritic cells [42,135]. The receptors PPARα, CB1, and CB2 that directly interact with endocannabinoids [132] are located in the bronchi of mice [136]. The endocannabinoid 2-AG and its receptor CB2 play an important role in the inhibition of mast cells (MC), as well as in the migration of eosinophils to the respiratory tract [137].…”

GPR6 Structural Insights: Homology Model Construction and Docking Studies

“…The hGPR6 homology model was constructed based upon the X-ray crystal structure of the Sphingosine-1-phosphate receptor 1 (S1P1) at a 2.8 Å resolution [PDB identifier: 3V2Y] [28]. S1P1 shares 33% sequence homology (similarity) with GPR6 sequence [14]. Both share essential features such as (1) the absence of helix kinking proline residues in TMH2 (2.58 or 2.59) and TMH5 (5.50), (2) the presence of an acidic residue E1.49 before the highly conserved N1.50 in TMH1 and (3) the presence of an internal disulfide bridge in the EC2 loop (see Supplementary Materials, Figure S1 for Human sequence alignments of S1P1 and GPR6 receptors).…”

“…While the G-protein independent signaling pathway via β-arrestin requires TMH7 movement to expose the extreme end of the C-terminus for the β-arrestin to couple with it [46]. GPR6 has been shown to signal via G-protein and to have high constitutive activity [14]. Activation via G-protein occurs upon changes in intrahelical interactions between TMH3 and TMH6 [47].…”

“…GPR6 is a Gαs-coupled receptor that its highly expressed in human striatum and hypothalamus [14]. It exhibits high constitutive activation of adenylyl cyclase, producing cyclic AMP (cAMP) levels that rival the cAMP levels produced by many fully activated Gαs-coupled receptors with their corresponding agonists [4,7,15].…”