Analysis of G-Protein Coupled Receptor 12

Analysis of G-Protein Coupled Receptor 12 ABSTRACT: G-Protein Coupled Receptor 12 (GPR12) belongs to the orphan GPCR family which is the same of the GPR3 and GPR6. Homology model for the protein GPR12 was generated from the SWISS-MODEL website which showed an all alpha motif with seven transmembrane ÃŽÂ ± -helix interconnected by loops. GPR12 acts through the cyclic Adenosine monophosphate (cAMP) pathway and promotes neurite outgrowth in primary neurons which can be used to slow down the progression of neurodegenerative diseases. The gene of GPR12 is located in the chromosome 13q12.13 for human, 12p11 for rat and 5; 5 G3 for a mouse with the size of 5.6 kbp, 3.4 kbp, and 4.3 kbp. Four current ongoing clinical trials studies on GPR12 was found on clinicaltrials.gov. G-Protein Coupled Receptor 12 (GPR12) belongs to the orphan GPCR family which is the same of the GPR3 and GPR6 (Ignatov et al., 2003a; Ignatov et al., 2003b). GPR 12 family members are constitutively activated and initiate the cAMP signaling cascades (Ignatov et al., 2003a). It is reported that GPR12 promote neurite extension in primary neurons (Ignatov et al., 2003a). The sequence identity of GPR12 is similar to GPCR S1P5 by 34%, GPR3 by 57% and GPR6 by 58% (Ignatov et al., 2003a; Ignatov et al., 2003b). Hence, it is hypothesized that the orphan receptors might share common ligands and also have similar physiological functions (Uhlenbrock et al., 2002; Tanaka et al., 2007). GPR12 has a high binding affinity towards Sphingosylphosphorylcholine (SPC) (Uhlenbrock et al., 2002). GPR 12 also binds with Sphingosine-1-phosphate (S1P)   with low affinity (Uhlenbrock et al., 2002). GPR12 family members are constantly activated and cAMP downstream signaling cascades initiated (Uhlenbro ck et al., 2002; Ignatov et al., 2003a). This persistent activation promotes neurite extension in primary neurons (Tanaka et al., 2007). GPR12 belongs to the orphan GPCR family which is the same of the GPR3 and GPR6 (Ignatov et al., 2003a; Ignatov et al., 2003b). According to Horn et al., GPR12 belongs to the  Ãƒâ€šÃ‚   GPCRs, Class A Rhodopsin-like subfamily with all other Orphan GPCR receptors (Horn et al., 2003). 2.1. Structure: A search was conducted for GPR12 in the RCSB protein data bank to identify the protein structure of G-Protein Coupled Receptor 12. There were no matches found in the search which is shown in figure 1.   Hence, a Homology model for the protein was generated from the SWISS-MODEL website, 27.41% sequence identity was indicated for Cannabinoid receptor 1 (Flavodoxin). Flavodoxin, Cannabinoid receptor one was chosen as the template, and a 3D structural model was generated for GPR12 from the template which is shown in the figures 2a and 2b. The GMQE (Global Model Quality Estimation) and Q-Mean value for the generated protein 0.56 and -4.28. The generated protein showed an all alpha motif with seven transmembrane ÃŽÂ ± -helix interconnected by loops forming four extracellular topological domains and four cytoplasmic topological domains. The alignment of protein sequence between Human GPR12 and GPR12 of other species like mouse and rat showed very less variation which indicates the protein is conserved between these species(UniProtKB; UniProtKB; UniProtKB). The protein alignment is shown in figure 3. 2.2. Pathway: According to Horn et al., GPR12 belongs to the  Ãƒâ€šÃ‚   GPCRs, Class A Rhodopsin-like subfamily with all other Orphan GPCR receptors (Horn et al., 2003). GPR12 acts through the cyclic Adenosine monophosphate (cAMP) pathway (Tanaka et al., 2007). Since, GPR12 is an orphan receptor where its natural ligand is unknown (Ignatov et al., 2003a). When the ligand such as S1P or SPC binds to the GPR12, the G-Protein gets activated due to the binding of GTP (Ignatov et al., 2003a). Thus, G-Protein activates Adenylate cyclase which converts the Adenosine triphosphate (ATP) into cAMP, and the cAMP activates Protein Kinase A (Ignatov et al., 2003a). The Activated Protein Kinase A activates the cellular reaction such as neurite extension in primary neurons (Ignatov et al., 2003a). [Refer figure 4] 2.3. Gene and Evolutionary aspects of GPR12: The alignment of protein sequence between Human GPR12 and GPR12 of other species like mouse and rat showed very less variation which indicates the protein is conserved between these species (UniProtKB; UniProtKB; UniProtKB). The protein alignment is shown in figure 3. The gene location of GPR12 in the chromosomes locus is nearly the same for human and rat, but it is different in mouse (NCBI-Gene; NCBI-Gene; NCBI-Gene). The gene of GPR12 is located in the chromosome 13q12.13 for human, 12p11 for rat and 5; 5 G3 for mouse (NCBI-Gene; NCBI-Gene; NCBI-Gene). The GPR12 gene contains two exons in humans, three exons in rat and three exons in Mouse separating the intron sequence and the evolutionary association of the gene sequence of GPR12 between the species and between GPCR family is shown in figure 5a and 5b (NCBI-Gene; NCBI-Gene; NCBI-Gene). The GPR12 gene size for a human is 5.6 kbp, for rat it is 3.4 kbp, and for the mouse, it is 4.3 kbp (NCBI-Gene; NCBI-Gene; NCBI-Gene; Stevens et a l., 2013). GPR12 mutant mice showed an effect in their emotionality was affected due to the mutation in GPR12 which was no significant change   (Frank et al., 2012). GPR12 overexpressed in neurons upregulate cAMP levels and promotes neurite outgrowth in primary neurons which can be used to slow down the progression of neurodegenerative diseases like Alzheimers disease, Parkinsons   disease, Huntingtons disease, etc. (Tanaka et al., 2007). GPR12 is also involved in the regulation of cell survival and cell proliferation which may vary during the diseased condition which causes astrocytes to proliferate at a faster rate and results in inflammation (Lu et al., 2012). A search was done for G-Protein coupled receptor 12 on clinicaltrails.gov website which showed four current ongoing clinical trials studies on GPR12. The studies were different from each other such as Platelet reactivity (ClinicalTrials.gov), Stoke (ClinicalTrials.gov), Metastatic Lung Adenocarcinomas (ClinicalTrials.gov) and Migraine (ClinicalTrials.gov). GPR12 belongs to the  Ãƒâ€šÃ‚   GPCRs, Class A Rhodopsin-like subfamily with all other Orphan GPCR receptors. The gene coding for GPR12 is conserved between Humans, Rats, and Mouse which indicates the existence of similar roles and function in these three animals. GPR12 is still in the stages of primary research where its structure, signaling pathways, function, and roles are still waiting to be found. GPR12 has recently assumed to be associated with Neural disorders and diseases. Clinical trials have been successfully conducted for GPR12 for many diseases one of which is depression. References: ClinicalTrials.gov Is There a Transient Rebound Effect of Platelet Reactivity Following Cessation of Dual Antiplatelet Therapy With Ticagrelor a Single Center Prospective Observational Trial. Journal, https://clinicaltrials.gov/ct2/show/NCT02808039?term=G-Protein%2BCoupled%2BReceptor%2B12recr=Openrank=1, January 25, 2017. ClinicalTrials.gov Platelet Reactivity in Acute Non-disabling Cerebrovascular Events (PRINCE). Journal, https://clinicaltrials.gov/ct2/show/NCT02506140?term=G-Protein+Coupled+Receptor+12recr=Openrank=2, January 25, 2017. ClinicalTrials.gov Retrospective Analysis of the Expression of the Neurotensin Receptor by Metastatic Lung Adenocarcinomas (NTS). Journal, https://clinicaltrials.gov/ct2/show/NCT02891733?term=G-Protein%2BCoupled%2BReceptor%2B12recr=Openrank=4, January 25, 2017. ClinicalTrials.gov Ticagrelor Therapy for RefrACTORy Migraine Study (TRACTOR). Journal, https://clinicaltrials.gov/ct2/show/NCT02518464?term=G-Protein%2BCoupled%2BReceptor%2B12recr=Openrank=3, January 25, 2017. Frank, E., Wu, Y., Piyaratna, N., Body, W.J., Snikeris, P., South, T., Gerdin, A.K., Bjursell, M., Bohlooly, Y.M., Storlien, L. Huang, X.F. (2012) Metabolic parameters and emotionality are little affected in G-protein coupled receptor 12 (Gpr12) mutant mice. PLoS One, 7, e42395. Horn, F., Bettler, E., Oliveira, L., Campagne, F., Cohen, F.E. Vriend, G. (2003) GPCRDB information system for G protein-coupled receptors. Nucleic acids research, 31, 294-297. Ignatov, A., Lintzel, J., Hermans-Borgmeyer, I., Kreienkamp, H.-J., Joost, P., Thomsen, S., Methner, A. Schaller, H.C. (2003a) Role of the G-protein-coupled receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its expression and function in brain development. Journal of Neuroscience, 23, 907-914. Ignatov, A., Lintzel, J., Kreienkamp, H.-J. Chica Schaller, H. (2003b) Sphingosine-1-phosphate is a high-affinity ligand for the G protein-coupled receptor GPR6 from mouse and induces intracellular Ca2+ release by activating the sphingosine-kinase pathway. Biochemical and Biophysical Research Communications, 311, 329-336. Lu, X., Zhang, N., Meng, B., Dong, S. Hu, Y. (2012) Involvement of GPR12 in the regulation of cell proliferation and survival. Mol Cell Biochem, 366, 101-110. NCBI-Gene Gpr12 G-protein coupled receptor 12 [Mus musculus (house mouse)] Gene NCBI. Journal, https://www.ncbi.nlm.nih.gov/gene/14738, January/25/2017. NCBI-Gene GPR12 G protein-coupled receptor 12 [Homo sapiens (human)] Gene NCBI. Journal, https://www.ncbi.nlm.nih.gov/gene/2835, January/25/2017. NCBI-Gene Gpr12 G protein-coupled receptor 12 [Rattus norvegicus (Norway rat)] Gene NCBI. Journal, https://www.ncbi.nlm.nih.gov/gene/80840, January/25/2017. Stevens, R.C., Cherezov, V., Katritch, V., Abagyan, R., Kuhn, P., Rosen, H. Wuthrich, K. (2013) The GPCR Network: a large-scale collaboration to determine human GPCR structure and function. Nat Rev Drug Discov, 12, 25-34. Tanaka, S., Ishii, K., Kasai, K., Yoon, S.O. Saeki, Y. (2007) Neural expression of G protein-coupled receptors GPR3, GPR6, and GPR12 up-regulates cyclic AMP levels and promotes neurite outgrowth. J Biol Chem, 282, 10506-10515. Uhlenbrock, K., Gassenhuber, H. Kostenis, E. (2002) Sphingosine 1-phosphate is a ligand of the human gpr3, gpr6 and gpr12 family of constitutively active G protein-coupled receptors. Cellular signalling, 14, 941-953. UniProtKB GPR12 G-protein coupled receptor 12 Homo sapiens (Human) GPR12 gene protein. Journal, http://www.uniprot.org/uniprot/P47775, January 25, 2017. UniProtKB Gpr12 G-protein coupled receptor 12 Mus musculus (Mouse) Gpr12 gene protein. Journal, http://www.uniprot.org/uniprot/P35412, January 25, 2017. UniProtKB Gpr12 G-protein coupled receptor 12 Rattus norvegicus (Rat) Gpr12 gene protein. Journal, http://www.uniprot.org/uniprot/P30951, January 25, 2017. Figure 1: No structure was found for the protein GPR12 in RCSB Protein data bank. Figure 2a: Side view of the GPR12 structure which was generated by SWISS-MODEL. The protein is showing an all alpha motif with seven transmembrane ÃŽÂ ± -helix interconnected by loops forming four extracellular topological domains and four cytoplasmic topological domains. Figure 2b: Top view of the GPR12 structure which was generated by SWISS-MODEL. The protein is showing an all alpha motif with seven transmembrane ÃŽÂ ± -helix interconnected by loops forming four extracellular topological domains and four cytoplasmic topological domains. Figure 3: GPR12 protein alignment for the species Human, mouse and rat generated from ClustalW. * (asterisk) indicates positions which have a single, fully conserved residue, : (colon) indicates conservation between groups of strongly similar residue properties, . (period) indicates conservation between groups of weakly similar residue properties. Figure 4: GPR12 proteins complete intracellular signaling pathway Figure 5a: Phylogenetic/evolutionary tree of GPCR family members (Stevens et al., 2013) Figure 5b: Phylogenetic/evolutionary tree of GPR12 showing evolutionary difference between human, rat, and mouse   Ã‚   G-Protein Coupled Receptor (GPR12) Protein Agonist Antagonist Sphingosine-1-phosphate Suramin Sphingosyl-phosphocholine Table 1: GPR12 agonist and antagonist with structure and name

Reflection of life Essay

America was put into a state of national depression in a matter of 24 hours. On October 29, 1929 millions of dollars was lost by the American economy in a time known as, the Wall Street Crash (this led to the Depression). Banks became bankrupt themselves and over 1/3 of the American population became redundant. The story ‘Of Mice and Men’ is set during the American Depression in the American countryside where both Lenny and George whom are ranch hands are going to their next job on Curly’s father’s farm. In the book, the economic depression is largely explored and has a great influence on the structure of the book. Both George and Lenny represented real – life ranch hands they had, ‘no family’ and ‘don’t belong no place. ’ Most men during the economic depression had little to go by in terms of money and work. Most ranchmen wasted their money, ’stake’ and had little going for them as only people who were educationally equipped and also financially sustained could live well. Ranchmen could only, ‘work up a stake and they go inta town and blow their stake, and the first thing you know they’re pundin’ their tail on some other ranch. They ain’t got nothing to look ahead to. ’ This became a reality in real – life as fewer jobs were permanent and the little pay that the ranchmen got was so small that the only way to spend it was on drink and brothels. The American Dream was depended on greatly by most of the population of America as at this time it acted like the thread of hope that could well have gotten many people out of the economically deprived state they seemed to be in. Both Lenny and George dreamed of owning a farm and living off, ‘the fatta the lan’. ’ This meant living for themselves and growing their own crops to live a self – sustainable independent life together. ‘I remember about the rabbits, George,’ this is a very significant line, it portrays the great hope that one can still have and that a dream can be achieved. The dream for Lenny and George was very humble. Lenny wanted to, ‘tend the rabbits’ and George hoped for a place to settle down. Lenny always remembers their dream as there was a chance it could have happened. During the depression many Americans became recluse to themselves, times were hard and what little could be gained was meant for an individual and their own loved ones, this isolation is represented when, ‘Candy spoke they both jumped as though they had been caught doing something reprehensible. ’ This shows that Lenny and George’s dream was meant for themselves not anybody else; they hoped to hide this from others so they can get their dream without others interfering and potentially messing it up. However Candy’s interference was worthwhile as it started to form their dream, ‘they fell into a silence. They looked at one another, amazed. This thing they had never really believed in was coming true. ’ This sheer excitement is a reflection of what small opportunities during this time made to an American’s life. Racism is greatly reflected in ‘Of Mice and Men,’ during the depression, racism was more evident in American society, especially against the black population who were racial segregated. Crooks the stable buck is a prime example of this as he has one of the lowest social statuses and is always referred to as, ‘nigger. ’ He is isolated from the rest of the ranch hands, â€Å"you don’t let me in your house to play cards, so why should I let you into my house? † This sentence reveals that this action bothers him so he does not want to interact with the people that are so socially unaware of the wrong they are doing. The ranch hands seem to be oblivious to the fact Crooks is a real person and even when Crooks was allowed to join in with the Christmas festivities, he was still caught up in some degradation as he became centred around a fight with one of the ranch hands. ‘Yes sir. Jesus, we had fun. They let the nigger come in that night. Little skinner name of Smitty took after the nigger. ’ Lastly, the lives of women are explored greatly. Women at this point were merely for show. There were no significant female leaders in America at this point and women like Curley’s wife were treated mainly as objects not real people. The life of Curly’s wife was very isolated. She was thought to cause trouble; this is because she was attractive and married to a man who wanted to pick a fight with anyone. A fight like that would easily arouse if a ranch hand handled Curley’s wife, â€Å"She’s gonna make a mess. They’s gonna be a bad mess about her. She’s a jail bait all set on the trigger. That Curley got his work cut out for him. Ranch with a bunch of guys on it ain’t no place for a girl, specially like her. † Curley’s wife is treated like trouble and because she is the only female on the ranch she is isolated. She has no female friends, men will fancy her, her husband has anger management issued and she has no morale guide. Women may have been treated more as trophy wives than they did before, â€Å"well – she got the eye,† this quote is said by Candy as a compliment. Overall Curly’s wife reflects closely to the prejudice that women could have faced but it was unlikely all women at the time would have been treated this badly, up to the point that she had been killed. In conclusion ‘Of Mice and Men’ is generally a thorough reflection of the period of time the book was written in. Both Black people and women were isolated in situations against white men who were largely dominant on a social front in the American economic depression.

Societys Influence on the Relationships in A Doll’s House...

Society shapes and molds both people and relationships in both good and bad ways. In a Doll’s House by Henrik Ibsen, Torvald and Nora’s relationship was destructive because of society, shown in the novel through symbols, motifs, and indirect characterization. Their relationship was ultimately strained by the views of others, society, showing that if marital views of society are embraced in a marriage, the marriage will fall apart. Torvald’s relationship with Nora was greatly affected by the views society had of women’s roles both in marriage and as a stereotypical stay-at-home mother. The destructive affect by society on the relationship of Torvald and Nora is shown in the play by symbolism. Torvald’s use of childlike and slightly condescending nicknames towards Nora shows how men viewed women as inferior. Torvald’s â€Å"pet† nicknames, as one would use these names to call a pet or a child, represents the submissive representation Torvald gives to both Nora and women in general by Torvald saying â€Å"Is it my little squirrel bustling about?† (Ibsen, 2) and â€Å"Is that my little lark twittering out there?† (2). These quotes show that Torvald uses submissive and child-like nicknames to show his superiority to Nora and the unequal marriage between Torvald and Nora. With one spouse as inferior, this shows how marriages are strained, as women in relationships wan t an equal relationship. Torvald’s nicknames to Nora symbolize the time period and the Victorian time, how men were the providersShow MoreRelatedHerik Ibsen: Father of Modern Drama1459 Words   |  6 Pages2013 Henrik Ibsen as â€Å"The Father of Modern Drama† Henrik Ibsen has long been referred to as the Father of Modern Drama, and such title has rightly been given so. 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The role of public relations in the shaping of news Free Essay Example, 3500 words

The media then acts as a force multiplier and consumes the media bandwidth with such parlous writing. Rationale public opinion is then moulded as the paid news acts as a puissant force to change public opinion. What is even worse is the end of creative writing and investigative journalism (Curtin and Rhodenbaugh, 2001). With this background, this paper examines a case study of Churnalism where parts of content from a PR release and reports were copied by other publications. The paper presents a chapter on the subject of PR and its importance, the perceived hostility of journalists towards PR followed by a detailed discussion of the case. The problem of assessing the authenticity and reliability of articles has become increasingly difficult. To bring some order into the system, many publications have come together to form the Sunlight Foundation's Churnalism website (Sunlight Foundation, 2014). The website uses an open source search engine that allows editors to check the authenticity of an article. They can enter large chunks of text into a text box given in a page of the website and click the submit button. We will write a custom essay sample on The role of public relations in the shaping of news or any topic specifically for you Only $17.96 $11.86/pageorder now The open source search engine then runs a check to evaluate the extent of match in the words and sentences with other content online. The website compares and checks the content against a large number of PR websites such as PR News Wire. PR News Web, Market Wire and others. Matching text from the document that is undergoing a test is displayed in yellow highlights. The technique is somewhat familiar to the online plagiarism-checking tool used in college, such as 'Turn it in'. In any case, the effort shows the extent to which Churnalism has impacted online publication. The Guardian first released the news about the churn detector and then the content was churned by many publications such as PCWorld, Boing Boing, Ars Technica, The Atlantic, Digital Trends and many other online newspapers, blogs and websites (Page, 2013). However, despite the availability of the churn detector, journalists continue their perchance of copy/ pasting news items. Many time s, the copied content can be rewritten and paraphrased with minimal effort and in a few minutes. However, journalists prefer to churnalise either out of laziness, indifference or they do not fear being caught. 1.1 Brief description of the Churnalism case The case study is actually a narration of events where a number of newspapers copied a report released by the Benenden Healthcare Society that released a report quoting a poll stating, "British women spend more money on their looks than their health" (Benenden Health, 2011).