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  • br Pharmacology br Background to GPR function br

    2022-06-20


    Pharmacology
    Background to GPR35 function
    The emerging function of GPR35 in the nervous system
    Conclusions The role of GPR35 in the modulation of synaptic transmission, neurogenic and inflammatory pain, and potential signalling pathways involved in these processes are beginning to emerge. There has previously been a disconnect between gene knock out, single nucleotide polymorphisms, and pathophysiological conditions associated with GPR35 versus the basic signal transduction pathways that emanate from this receptor under normal physiological conditions (Mackenzie et al., 2011). With the most recent findings suggesting a GPR35-Gαi/o-linked mechanism of inhibition of synaptic transmission, and possible regulation of GPR35 by Ret tyrosine kinase (Franck et al., 2011) and hypoxia (Ronkainen et al., 2014) we are beginning to discern the basic signalling pathways of GPR35 and processes regulating it's expression. This exciting new avenue of research expands the potential therapeutic value of GPR35 beyond that as a target for the treatment of heart failure and hypertension (Min et al., 2010, Sun et al., 2008). However, close attention to the pharmacological differences between species orthologues of GPR35 is required to better validate conclusions and the use of both Pirarubicin and tissues from knock out animals will be vital to overcome concerns about effects of GPR35 active ligands reflecting non-GPR35 mediated mechanisms.
    Conflict of interest statement
    Acknowledgements This work was supported by a Scottish Universities Life Sciences Alliance (SULSA), Merck Sharp and Dohme (169339-01) fellowship. This work is part-funded by the MSD Scottish Life Sciences fund. As part of an on-going contribution to Scottish life sciences, Merck Sharp & Dohme Limited (MSD), a global healthcare leader, has given substantial monetary funding to the Scottish Funding Council (SFC) for distribution via the Scottish Universities Life Science Alliance (SULSA) to develop and deliver a high quality drug discovery research and training programme. All aspects of the programme have been geared towards attaining the highest value in terms of scientific discovery, training and impact. The opinions expressed in this research are those of the authors and do not necessarily represent those of MSD, nor its Affiliates.
    Introduction G protein-coupled receptor (GPCR)35 is one of the “orphan” GPCR [1] that shares homology with subtypes of the purinergic (GPR23/P2Y9) [2], nicotinic acid (HM74) [3], and lysophosphatidylinositol (GPR55) [4] receptors. The chromosomal mapping of GPR35 and its association with a number of human diseases have been largely investigated [5], while its expression and pharmacological characterization remains to be fully defined. The identification of l-kynurenic acid (KYNA) [6], an endogenous product of the l-tryptophan catabolism (kynurenine pathway), and 2-acyl lysophosphatidic acid (LPA) [7], an endogenous molecule generated via a phospholipase A1-dependent pathway from PA, as selective ligands for GPR35 led to its deorphanization and characterization. GPR35 preferentially couples with Gi/o proteins in GPR35-transfected Chinese hamster ovary cells [6], as well as in cells constitutively expressing this receptor (e.g., rat sympathetic [8] and dorsal root ganglion neurons [9], human monocytes [10]). The expression analysis of human and mouse GPR35 revealed that it is predominantly expressed in immune and gastrointestinal systems. Among immune cells, GPR35 is highly expressed in human CD14+ monocytes, T cells, neutrophils, and dendritic cells (DC), with lower expression levels in B cells, eosinophils, basophils, and platelets [6], [10]. iNKT cells are a unique autoreactive cluster of differentiation 1 (CD1)d-restricted T cell subpopulation, characterized by the expression of an invariant T cell receptor (TCR) alpha chain, (Vα14–Jα18 in mice, and Vα24–Jα18 in humans), in combination with typical surface receptors of natural killer (NK) cells [11].