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  • The finding that GPR acts as a receptor for acyl


    The finding that GPR35 acts as a receptor for 2-acyl LPA is noteworthy, because P2Y5, which has homology with GPR35 (29%), has recently been shown to act as a receptor for 2-acyl LPA [14]. LPA3 is also a specific receptor for 2-acyl LPA [15]. It is also worth noting that GPR55, which has homology with GPR35, is a specific and functional receptor for 2-acyl LPI, i.e., 2-arachidonoyl LPI [10]. These G protein-coupled receptors (GPR35, P2Y5, GPR55 and LPA3) may comprise a novel family of 2-acyl lysophospholipid receptors. As for 2-acyl LPA, we have demonstrated that a substantial amount of 2-arachidonoyl LPA is present in the rat brain [16]. Polyunsaturated fatty acid-containing species of LPA, such as arachidonoyl LPA, were also shown to occur in several biological fluids [17], [18]. It should be noted that several types of phospholipase A1, which act on PA, have already been reported [19], [20]. These phospholipases selectively generate 2-acyl LPA from the PA molecule. This reaction is one of the main pathways for the synthesis of LPA in mammalian tissues. In any case, it seems that 2-acyl LPA is a rather common molecule, and 2-acyl LPA, generated via a phospholipase A1-dependent pathway, exhibits biological activities by acting on specific receptors, such as P2Y5 and GPR35, in several mammalian tissues and cells. GPR35 is expressed in gastrointestinal tissues, including the small intestine and colon, lymphoid tissues, such as the spleen and thymus, and peripheral blood leukocytes [1], [2], [4]. It is also expressed in rat dorsal root ganglion neurons [3]. Several lines of evidence suggest that GPR35 is involved in nociception [3], the regulation of neuronal excitability and synaptic release [5], and the recruitment of leukocytes [21]. However, these studies were conducted using kynurenic dub inhibitor and/or zaprinast but not 2-acyl LPA as the ligand. Intriguingly, GPR35 may be involved in the pathogenesis of the Albright hereditary osteodystrophy-like phenotype or brachydactyly-mental retardation syndrome [6], coronary artery calcification [22], type-2 diabetes [23] and heart failure [7]. It should also be noted that the GPR35 gene functions to transform NIH3T3 cells, and its expression was markedly up-regulated in gastric cancer cells [4].
    Introduction GPR35 is a poorly characterized 7-transmembrane domain G protein-coupled receptor (GPCR) first identified more than 10years ago. It was derived from an open reading frame corresponding to 309 amino acids located in humans on chromosome 2, region q37.3 [1]. In these initial studies, expression was examined in a range of tissues but was detected only in the intestine of the rat; it was also reported to be lacking in a number of regions of human brain [1]. Subsequently, this same sequence (and a further sequence encoding a second form of GPR35 that appears to be a differentially spliced isoform containing an N-terminal extension of 31 amino acids) (Figure 1) was identified from a cDNA library produced from human gastric cancer cells [2]. Again, expression was also detected in normal intestinal mucosal cells [2], and because these cDNAs were able to transform NIH-3T3 cells, it was suggested that GPR35 might be oncogenic and play a role in the generation of gastric cancers [2]. The significance of the N-terminally extended form of GPR35 remains to be defined, but messenger RNA encoding this variant has been reported to be present at higher levels than the shorter form [2]. In humans, the GPR35 gene displays significant polymorphic variability, with a number of non-synonymous variants within the open reading frame resulting in alterations in amino acid sequence 3, 4 (Figure 1). However, to date, apart from a very cursory examination of the Ser294Arg variant [5], which has been associated with the propensity to develop coronary artery calcification [6] (Table 1), effects of these variations on signal transduction and pharmacology have yet to be reported. A further single nucleotide polymorphism, located in the 5′’ untranslated region of the GPR35 gene, has been linked to early-onset inflammatory bowel disease in a genome-wide association study [7] but no further information on this is currently available.