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Lipid sensing G protein-coupled receptors in the CNS
Neuropharmacology 113 (2017) 595e596
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Editorial
Lipid sensing G protein-coupled receptors in the CNS
Lipid-sensing G protein-coupled receptors (GPCRs) expressed in the central nervous system (CNS) represent a diverse and exciting new family of transmembrane proteins that have been show to modulate neuronal function and glia cell biology. This disparate grouping represents an important opportunity for drug development in CNS-related illnesses and in particular for neuroinflammatory-related disease. Drugs targeting some of these receptors are now well established in the clinic, while other members of this family have been emerging from the orphan GPCR grouping and represent promising drug targets for the future. This Special Issue attempts to convey the current status of this field, highlighting examples that range from target validation to clinical stages. One of the main lipid-sensing GPCRs that has successfully reached the clinic through the development of small molecule ligands is the sphingosine 1-phosphate receptor (S1PR). This topic is addressed by O'Sullivan and Dev (2017), where they focus on the S1PR drug, fingolimod, briefly describing its success as the first oral therapy used in patients with multiple sclerosis and summarising its potential use in a range of other neurological, neurodegenerative and psychiatric illnesses. In this series, the therapeutic potential of lysophosphatidic acid receptors (LPARs), a close relative of S1PR's and belonging to the EDG family of GPCRs, are also presented. Here, the role of LPARs in pain, myelination state and regulation of microglia activation is discussed by Sheridan and colleagues (Velasco et al., 2017). Cannabinoid receptors (CBRs) respond to endogenous lipidamides and have received significant attention since their first identification in the early 1990s. To date, targeting the CBRs has offered limited clinical success for CNS disease, where, for example, the cannabis extract Sativex provides only symptomatic relief in multiple sclerosis and little effect on disease progression. However, as we continue to understand more about the role of CBRs and the endocannabinoid system, new opportunities are clearly arising. The manuscript presented by Fitzpatrick & Downer (Fitzpatrick and Downer, 2017) describes a novel interaction between the endocannabinoid system and toll-like receptor signalling and suggests that compounds targeting this interaction may provide a useful therapeutic strategy. This Special Issue also presents a role for CBRs, particularly CB2R agonists, as drug targets for regulating inflammatory processes in the eye and for potential use in diseases such as
http://dx.doi.org/10.1016/j.neuropharm.2016.10.030 0028-3908/© 2016 Published by Elsevier Ltd.
proliferative vitreoretinopathy (PVR) and loss of vision (Szczesniak et al., 2017). Lipid-sensing receptors emerging from the orphan GPCR grouping are offering exciting new opportunities, both in basic research and as drug targets, aided primarily by the development of new pharmaceutical agents, data from knockout studies and genetic linkages to human disease. We have selected three examples from this emerging area, namely GPR40, GPER1, GPR35. In the first of these examples, the article on GRP40 (also called free fatty acid receptor 1, FFA1) provides a good illustration of an orphan GPCR with considerable potential in the clinic (Khan and He, 2017). This receptor recognises polyunsaturated fatty acids as ligands and has been suggested to play a role in neuronal function and diseases such as inflammatory pain, Alzheimer's disease and Parkinson's disease. The second of these examples describes the receptor, GPER (also known as GPR30), that may mediate many of the non-genomic effects of estrogen in the CNS and could be a useful target for diseases of cognitive function and neurodegeneration (Alexander et al., 2017). In the third example, Mackenzie and Milligan, (2017) describe GPR35 as an atypical LPA receptor, which plays a role in nociception and has interesting genetic linkages to a variety of diseases. We note these articles provide only an insight into lipid-sensing GPCRs. Other receptors in this category that we encourage readers to explore, include EBI2, GPR55, GPR18 and OGR1 (GPR68). The role of these receptors in the CNS is only just emerging; however they highlight a rapidly developing field. The aim of this Special Issue has been to showcase the potential of lipid-sensing receptors that are expressed in the CNS. It is notable that many of these receptors have also a prominent localization on cells within the immune system and may therefore represent drug targets that have a multimodal effect that is particularly relevant to neuroinflammatoryrelated disease and the regulation of neuron-immune cell/glia interactions.
References Alexander, A., Irving, A.J., Harvey, J., 2017. Emerging roles for the novel estrogensensing receptor GPER1 in the CNS. Neuropharmacology 113, 652e660. Fitzpatrick, J-M.K., Downer, E.J., 2017. Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis. Neuropharmacology 113, 618e626.
596
Editorial / Neuropharmacology 113 (2017) 595e596
Khan, M.Z., He, L., 2017. The role of polyunsaturated fatty acids and GPR40 receptor in brain. Neuropharmacology 113, 639e651. Mackenzie, A.E., Milligan, G., 2017. The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 113, 661e671. O'Sullivan, S., Dev, K.K., 2017. Sphingosine-1-phosphate receptor therapies: advances in clinical trials for CNS-related diseases. Neuropharmacology 113, 597e607. Szczesniak, A.M., Porter, R.F., Toguri, J.T., Borowska-Fielding, J., Gebremeskel, S., Siwakoti, A., Johnston, B., Lehmann, C., Kelly, M.E.M., 2017. Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy. Neuropharmacology 113, 627e638. Velasco, M., O'Sullivan, C., Sheridan, G.K., 2017. Lysophosphatidic acid receptors (LPARs): potential targets for the treatment of neuropathic pain. Neuropharmacology 113, 608e617.
K.K. Dev Drug Development, School of Medicine, Trinity College Dublin, Dublin, Ireland A.J. Irving* School of Biomolecular and Biomedical Science, University College Dublin, Ireland * Corresponding author. E-mail address: [email protected] (A.J. Irving).
Contents lists available at ScienceDirect
Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm
Editorial
Lipid sensing G protein-coupled receptors in the CNS
Lipid-sensing G protein-coupled receptors (GPCRs) expressed in the central nervous system (CNS) represent a diverse and exciting new family of transmembrane proteins that have been show to modulate neuronal function and glia cell biology. This disparate grouping represents an important opportunity for drug development in CNS-related illnesses and in particular for neuroinflammatory-related disease. Drugs targeting some of these receptors are now well established in the clinic, while other members of this family have been emerging from the orphan GPCR grouping and represent promising drug targets for the future. This Special Issue attempts to convey the current status of this field, highlighting examples that range from target validation to clinical stages. One of the main lipid-sensing GPCRs that has successfully reached the clinic through the development of small molecule ligands is the sphingosine 1-phosphate receptor (S1PR). This topic is addressed by O'Sullivan and Dev (2017), where they focus on the S1PR drug, fingolimod, briefly describing its success as the first oral therapy used in patients with multiple sclerosis and summarising its potential use in a range of other neurological, neurodegenerative and psychiatric illnesses. In this series, the therapeutic potential of lysophosphatidic acid receptors (LPARs), a close relative of S1PR's and belonging to the EDG family of GPCRs, are also presented. Here, the role of LPARs in pain, myelination state and regulation of microglia activation is discussed by Sheridan and colleagues (Velasco et al., 2017). Cannabinoid receptors (CBRs) respond to endogenous lipidamides and have received significant attention since their first identification in the early 1990s. To date, targeting the CBRs has offered limited clinical success for CNS disease, where, for example, the cannabis extract Sativex provides only symptomatic relief in multiple sclerosis and little effect on disease progression. However, as we continue to understand more about the role of CBRs and the endocannabinoid system, new opportunities are clearly arising. The manuscript presented by Fitzpatrick & Downer (Fitzpatrick and Downer, 2017) describes a novel interaction between the endocannabinoid system and toll-like receptor signalling and suggests that compounds targeting this interaction may provide a useful therapeutic strategy. This Special Issue also presents a role for CBRs, particularly CB2R agonists, as drug targets for regulating inflammatory processes in the eye and for potential use in diseases such as
http://dx.doi.org/10.1016/j.neuropharm.2016.10.030 0028-3908/© 2016 Published by Elsevier Ltd.
proliferative vitreoretinopathy (PVR) and loss of vision (Szczesniak et al., 2017). Lipid-sensing receptors emerging from the orphan GPCR grouping are offering exciting new opportunities, both in basic research and as drug targets, aided primarily by the development of new pharmaceutical agents, data from knockout studies and genetic linkages to human disease. We have selected three examples from this emerging area, namely GPR40, GPER1, GPR35. In the first of these examples, the article on GRP40 (also called free fatty acid receptor 1, FFA1) provides a good illustration of an orphan GPCR with considerable potential in the clinic (Khan and He, 2017). This receptor recognises polyunsaturated fatty acids as ligands and has been suggested to play a role in neuronal function and diseases such as inflammatory pain, Alzheimer's disease and Parkinson's disease. The second of these examples describes the receptor, GPER (also known as GPR30), that may mediate many of the non-genomic effects of estrogen in the CNS and could be a useful target for diseases of cognitive function and neurodegeneration (Alexander et al., 2017). In the third example, Mackenzie and Milligan, (2017) describe GPR35 as an atypical LPA receptor, which plays a role in nociception and has interesting genetic linkages to a variety of diseases. We note these articles provide only an insight into lipid-sensing GPCRs. Other receptors in this category that we encourage readers to explore, include EBI2, GPR55, GPR18 and OGR1 (GPR68). The role of these receptors in the CNS is only just emerging; however they highlight a rapidly developing field. The aim of this Special Issue has been to showcase the potential of lipid-sensing receptors that are expressed in the CNS. It is notable that many of these receptors have also a prominent localization on cells within the immune system and may therefore represent drug targets that have a multimodal effect that is particularly relevant to neuroinflammatoryrelated disease and the regulation of neuron-immune cell/glia interactions.
References Alexander, A., Irving, A.J., Harvey, J., 2017. Emerging roles for the novel estrogensensing receptor GPER1 in the CNS. Neuropharmacology 113, 652e660. Fitzpatrick, J-M.K., Downer, E.J., 2017. Toll-like receptor signalling as a cannabinoid target in Multiple Sclerosis. Neuropharmacology 113, 618e626.
596
Editorial / Neuropharmacology 113 (2017) 595e596
Khan, M.Z., He, L., 2017. The role of polyunsaturated fatty acids and GPR40 receptor in brain. Neuropharmacology 113, 639e651. Mackenzie, A.E., Milligan, G., 2017. The emerging pharmacology and function of GPR35 in the nervous system. Neuropharmacology 113, 661e671. O'Sullivan, S., Dev, K.K., 2017. Sphingosine-1-phosphate receptor therapies: advances in clinical trials for CNS-related diseases. Neuropharmacology 113, 597e607. Szczesniak, A.M., Porter, R.F., Toguri, J.T., Borowska-Fielding, J., Gebremeskel, S., Siwakoti, A., Johnston, B., Lehmann, C., Kelly, M.E.M., 2017. Cannabinoid 2 receptor is a novel anti-inflammatory target in experimental proliferative vitreoretinopathy. Neuropharmacology 113, 627e638. Velasco, M., O'Sullivan, C., Sheridan, G.K., 2017. Lysophosphatidic acid receptors (LPARs): potential targets for the treatment of neuropathic pain. Neuropharmacology 113, 608e617.
K.K. Dev Drug Development, School of Medicine, Trinity College Dublin, Dublin, Ireland A.J. Irving* School of Biomolecular and Biomedical Science, University College Dublin, Ireland * Corresponding author. E-mail address: [email protected] (A.J. Irving).