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  • br Expression profile of GPR As noted above initial

    2021-09-22


    Expression profile of GPR35 As noted above, initial studies indicated expression of GPR35 in rat intestine [1] and stomach [2]. Subsequent studies have confirmed significant expression levels in the small intestine, colon and stomach, and this might be relevant in the association between a GPR35 polymorphic variant and early-onset inflammatory bowel disease [7]. GPR35 is also expressed in a range of other rat tissues including lung, uterus, dorsal root ganglion and spinal cord 22, 32. Wang et al.[8] were the first to record expression in the spleen and white cells in both humans and mice, whereas Yang et al.[33] have demonstrated that GPR35 is expressed in human mast cells, basophils and eosinophils, and that GPR35 mRNA is upregulated upon challenge with IgE antibodies. Furthermore, Barth et al.[34] have suggested that GPR35 is highly expressed by human peripheral monocytes, and messenger RNA encoding GPR35 is upregulated substantially in primary human macrophages exposed to benzo(α)pyrene [35]. The functional significance of this has not yet been reported.
    Physiological roles of GPR35 and potential therapeutic opportunities The expression of GPR35 in pancreatic β-cells, coupled with the ability of thiazolidinedione ligands that have agonist action at GPR35 to enhance glucose-stimulated insulin release in model cell lines and to improve oral glucose tolerance tests [25], has suggested a potential use for agonists of GPR35 in the treatment of diabetes and related metabolic disorders (Table 2). Expression of GPR35 in the intestine and colon might also be relevant because other GPCRs expressed on β-cells that regulate insulin secretion, such as FFA1 (also designated GPR40), are also expressed on enteroendocrine cells and regulate the secretion of incretins such as GLP-1 [36], hence providing dual pathways of control. This is also true of the free fatty BTB06584 receptor GPR120 [37], and could be a general property of GPCRs that link nutrient sensing and energy homeostasis. Although the specific distribution of GPR35 within the gut remains unclear, this is important to understand. Further studies using GPR35 agonists unrelated to the thiazolidinediones will also be vital to better define the contribution of GPR35 to the control of insulin secretion. GPR35 has also been implicated recently in the control of blood pressure. GPR35 was identified in an effort to explore genes associated with heart failure [38], but this was a poorly powered study involving only 12 patients with a variety of underlying conditions and marked differences in disease severity. More interestingly and convincingly, the blood pressure of mice lacking expression of GPR35 was reported to be elevated by 37.5mmHg compared with wild-type littermates [38]. GPR35 agonists might therefore be anticipated to lower blood pressure. Substantial numbers of patients have poorly controlled hypertension despite the use of combinations of current front-line therapies, so new therapeutic targets are needed for this population. Although evidence of involvement of GPR35 is preliminary, this receptor is clearly worthy of study in this area. The identification of both cromolyn disodium 23, 33 and nedocromil sodium [33] as GPR35 agonists (Table 1) is of particular clinical interest. Both of these drugs are approved anti-asthma medications and regulators of mast cell sensitization and histamine release. However, they are considered orphan drugs because their mode of action has been unclear. The fact that they can be shown to have agonist action at GPR35 in cells transfected to express this receptor does not mean that their mechanism of action in vivo has been defined. However, as noted above, various white blood cells, including mast cells, do express GPR35 and the growing availability of both agonist and antagonist ligands will allow the contribution of GPR35 to the therapeutic actions of cromolyn disodium and nedocromil sodium to be more fully assessed.