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  • Although it is currently unknown

    2022-05-13

    Although it is currently unknown why the longer splice variant found in the human has not been found in any other species, similar results have been reported for other receptors, including the Ristocetin A sulfate receptor splice variant ERbeta2 identified in human and primate, but not other species (Sierens, et al., 2004), as well as proteins like Smad6B, a negative regulator of TGF-beta signaling found only in human (Konrad, et al., 2008). The functional significance of the two GPR120 receptor variants in humans is unknown, although when the NM_181745 receptor reported by Hirasawa was transfected into HEK cells, it was co-expressed with the promiscuous G-protein Gα16 (Hirasawa et al., 2005, supplementary table 1), suggesting that the signaling of this variant is impaired. So although the receptor is expressed in vivo, it may not be fully functional to engage the signaling cascade leading to intracellular calcium release. A recent review (Morgan and Dhayal, 2009), reported that only the short form variant BC101175 was found in human pancreatic beta cells, which supports the notion that the long form NM_181745 may not have a functional role in this tissue. Further studies designed to examine the signaling properties, as well as the expression levels, of these two splice variants are ongoing. Several SNPs have been reported for a number of GPCR receptors such as GPR40 (Hamid et al., 2005). To ensure that the more prevalent form of the cynomolgus monkey sequence was cloned, several cynomolgus monkey samples were sequenced to determine the possibility of any other SNPs occurring. Since no non-synonymous SNPs discovered had allele frequencies of greater than 4%, it was determined that the cynomolgus monkey receptor sequence cloned was the more commonly occurring sequence. This conclusion was drawn based on the available population of 94 cynomolgus monkey samples that were studied. Additional studies in a wider population would have to be performed in order to confirm this conclusion more concretely. In the real-time PCR experiments performed to determine the tissue distribution of GPR120 in the cynomolgus monkey, it was found that the GPR120 receptor is more prevalent in colon and lung tissue than any other tissues tested. Previous studies in mouse and human tissues showed that levels of GPR120 mRNA were higher in lung, intestine, and colon tissue compared to other tissues (Hirasawa et al, 2005). In the rat, it was found that GPR120 was much more abundant in colon than in the lung (Tanaka et al., 2008). Therefore, the GPR120 receptor tissue profile of the monkey is fairly similar to the tissue profile of mice, humans, and rats. Since GPR120 receptor activation has been shown to cause GLP-1 release from mouse intestinal cells, it is not unexpected that there are abundant amounts of GPR120 mRNA found in the colon. In addition, the level of GPR120 mRNA was higher in the stomach of the cynomolgus monkey compared to the mouse and rat studies published which showed very little GPR120 mRNA in the stomach (Tanaka et al., 2008). The potential function of GPR120 in the stomach has been studied in mouse cells. Some studies have shown that free fatty acids play a role in preventing apoptosis in murine serum-starved STC-1 enteroendocrine cells located in the stomach when they activate GPR120 receptors (Katsuma et al., 2005). Another goal of the present studies was to create a pharmacological profile of fatty acids of varying chain lengths at the cynomolgus monkey GPR120 receptor compared with those expressing the human GPR120 (BC101175) receptor using the FLIPR to measure intracellular calcium release, which activates the signaling cascade through PKC. Long-chain unsaturated fatty acids such as linolenic acid and docosahexanoic acid caused the greatest amount of calcium efflux at the monkey GPR120 receptor. The calcium efflux measured by FLIPR in response to long-chain unsaturated fatty acids was similar in HEK 293 cells stably expressing the cynomolgus monkey GPR120 receptor as those expressing the human (BC101175) variant of GPR120. The high homology between these receptors (97.5%) confirms this finding. Compared to other fatty acids, linolenic acid has been shown to cause the highest level of intracellular calcium release at the cynomolgus monkey GPR120 receptor and both human GPR120 receptor isoforms (BC101175 and NM_181745 forms) (Hirasawa et al., 2005), and the rat GPR120 (Tanaka et al., 2008) receptor. Linolenic acid is an unsaturated 18 carbon fatty acid present in vegetable cooking oils and other plant products. Interestingly, clinical trials and experiments have shown that linolenic acid consumed in the diet may reduce the risk of myocardial infarction (Campos et al, 2008).