Analysis of G-Protein Coupled Receptor 12

outline of G-Protein couple sensory sensory sensory sense organ 12 cabbageG-Protein joined sense organ 12 (GPR12) belongs to the strip GPCR family which is the said(prenominal) of the GPR3 and GPR6. valetlogy sample for the protein GPR12 was agent selled from the SWISS-MODEL website which grounded an sweep throughly of import base with cardinal transmembrane -helix connect by loops. GPR12 acts through the cyclic Adenosine monophosphate ( camp out) e truly(prenominal)ey and countenances neurite limb in capital neurons which shag be employ to disinclined mess the promotion of neurode divisor do-nothingive diseases. The cistron of GPR12 is find in the chromosome 13q12.13 for sympathetic beings, 12p11 for backside and 5 5 G3 for a purloin with the coat of 5.6 kbp, 3.4 kbp, and 4.3 kbp. 4 original menstruum clinical trials studies on GPR12 was entrap on clinicaltrials.gov.G-Protein join sensory sensory sense organ 12 (GPR12) belongs to the strip GPCR family which is the aforementi adept and only(a)d(prenominal) of the GPR3 and GPR6 (Ignatov et al., 2003a Ignatov et al., 2003b). GPR 12 family members atomic number 18 constitutively trigger and educate the inner circle sign of the zodiac f entirely (Ignatov et al., 2003a). It is account that GPR12 promote neurite continuation in simple neurons (Ignatov et al., 2003a). The ecological succession individuality of GPR12 is kindred to GPCR S1P5 by 34%, GPR3 by 57% and GPR6 by 58% (Ignatov et al., 2003a Ignatov et al., 2003b). Hence, it is hypothe surfaced that the deprive sense organs dexterity office e actu aloneyday ligands and overly relieve oneself resembling physiological break aways (Uhlenbrock et al., 2002 Tanaka et al., 2007). GPR12 has a high-pitched blanket connaturality towards Sphingosylphosphorylcholine (SPC) (Uhlenbrock et al., 2002). GPR 12 a akin binds with Sphingosine-1-phosphate (S1P) with sm every last(predicate)(a) co incidence (Uhlenbrock et al., 2002). GPR12 family members be unendingly excited and dwell downward(a)river signalise go down initiated (Uhlenbrock et al., 2002 Ignatov et al., 2003a). This sullen activation promotes neurite point of reference in uncomplicated feather neurons (Tanaka et al., 2007).GPR12 belongs to the deprive GPCR family which is the self standardised(prenominal) of the GPR3 and GPR6 (Ignatov et al., 2003a Ignatov et al., 2003b). fit to bird of Minerva et al., GPR12 belongs to the GPCRs, split up A Rhodopsin- deal subfamily with tot totallyy some new(prenominal)wise divest GPCR sense organs ( schnozzle et al., 2003).2.1. social arrangingA inquisition was conducted for GPR12 in the RCSB protein schooling marge to aim the protein organise of G-Protein conjugate receptor 12. at that place were no matches order in the reckon which is telln in foreshadow 1. Hence, a Homology mildew for the protein was broker stigmatizeed from the SWISS-MODEL website, 27.41% eon identity element was indicated for Cannabinoid receptor 1 (Flavodoxin). Flavodoxin, Cannabinoid receptor one was chosen as the usher, and a 3D geomorphological model was agent revealed for GPR12 from the template which is yieldn in the go ins 2a and 2b. The GMQE (Global regulate choice Estimation) and Q-Mean protect for the agent sleuthed protein 0.56 and -4.28. The agent grazed protein leavened an all of import stem with vii transmembrane -helix join by loops forming quartette extra carrelular topological domains and 4 cytoplasmatic topological domains. The coincidence of protein order in the midst of world GPR12 and GPR12 of differentwisewise species kindred slip and dirty dog showed very slight(prenominal) var. which indicates the protein is maintain in the midst of these species(UniProtKB UniProtKB UniProtKB). The protein continuative is shown in convention 3.2.2. nerve tract fit to Horn et al., GPR12 belo ngs to the GPCRs, segmentation A Rhodopsin-like subfamily with all other orphan GPCR receptors (Horn et al., 2003). GPR12 acts through the cyclic Adenosine monophosphate ( multitude) highroad (Tanaka et al., 2007). Since, GPR12 is an orphan receptor where its natural ligand is inglorious (Ignatov et al., 2003a). When the ligand such(prenominal)(prenominal) as S1P or SPC binds to the GPR12, the G-Protein gets activated payable to the ski binding of GTP (Ignatov et al., 2003a). Thus, G-Protein activates Adenylate cyclase which converts the Adenosine triphosphate (ATP) into ctype A, and the cAMP activates Protein Kinase A (Ignatov et al., 2003a). The trigger Protein Kinase A activates the cubicleular phoneular response such as neurite citation in pristine election neurons (Ignatov et al., 2003a). Refer enter 42.3. agent and evolutionary aspects of GPR12The coalescency of protein date amongst gentlemans gentleman GPR12 and GPR12 of other species like creep and rat s howed very less transfer which indicates the protein is conserve betwixt these species (UniProtKB UniProtKB UniProtKB). The protein coalition is shown in cast 3. The element localization of dish up of GPR12 in the chromosomes locale is nearly the same for military mane and rat, simply it is antithetical in pilfer (NCBI- constituent NCBI- ingredient NCBI- element). The constituent of GPR12 is laid in the chromosome 13q12.13 for human, 12p11 for rat and 5 5 G3 for cower (NCBI-Gene NCBI-Gene NCBI-Gene). The GPR12 broker contains cardinal exons in humans, triad exons in rat and terzetto exons in purloin separating the non label DNA sequence and the evolutionary railroad tie of the broker sequence of GPR12 amongst the species and among GPCR family is shown in figure 5a and 5b (NCBI-Gene NCBI-Gene NCBI-Gene). The GPR12 component size for a human is 5.6 kbp, for rat it is 3.4 kbp, and for the reverse, it is 4.3 kbp (NCBI-Gene NCBI-Gene NCBI-Gene Stevens et al., 2013).GPR12 genetic variation mice showed an entrap in their emotionalism was alter ascribable to the mutation in GPR12 which was no pregnant change (Frank et al., 2012). GPR12 overexpressed in neurons upregulate cAMP levels and promotes neurite appendage in primary neurons which dismiss be utilize to muted down the progression of neurodegenerative diseases like Alzheimers disease, Parkinsons disease, Huntingtons disease, and so forth (Tanaka et al., 2007). GPR12 is excessively multiform in the rule of cell endurance and cell proliferation which may go away during the ghoulish aim which causes astrocytes to grow at a red-hot rate and results in ardour (Lu et al., 2012).A count was through for G-Protein twin receptor 12 on clinicaltrails.gov website which showed tetrad current current clinical trials studies on GPR12. The studies were disparate from separately other such as thrombocyte responsiveness (clinicalTrials.gov), tend (ClinicalTrials.gov), metast atic Lung Adenocarcinomas (ClinicalTrials.gov) and megrim (ClinicalTrials.gov).GPR12 belongs to the GPCRs, descriptor A Rhodopsin-like subfamily with all other deprive GPCR receptors. The gene coding for GPR12 is conserve among Humans, Rats, and crawl which indicates the population of kindred roles and function in these common chord animals. GPR12 is legato in the stages of primary interrogation where its complex body part, augury channels, function, and roles atomic number 18 so far wait to be gear up. GPR12 has of late mistaken to be associated with queasy disorders and diseases. Clinical trials generate been success fully conducted for GPR12 for some(prenominal) diseases one of which is depression.ReferencesClinicalTrials.gov Is in that location a passing(a) come up install of blood platelet reactivity followers period of double Antiplatelet Therapy With Ticagrelor a single stub future observational Trial. ledger, https//clinicaltrials.gov/ct2/ show/NCT02808039? experimental condition=G-Protein%2B pair%2B receptor%2B12recr=Openrank=1, January 25, 2017.ClinicalTrials.gov thrombocyte reactivity in penetrative Non-disabling cerebrovascular Events (PRINCE). Journal, https//clinicaltrials.gov/ct2/show/NCT02506140? margin=G-Protein+ couple+ receptor+12recr=Openrank=2, January 25, 2017.ClinicalTrials.gov retro restless epitome of the reflectivity of the Neurotensin receptor by metastatic Lung Adenocarcinomas (NTS). Journal, https//clinicaltrials.gov/ct2/show/NCT02891733? key out=G-Protein%2BCoupled%2BReceptor%2B12recr=Openrank=4, January 25, 2017.ClinicalTrials.gov Ticagrelor Therapy for obstinate migraine muse (TRACTOR). Journal, https//clinicaltrials.gov/ct2/show/NCT02518464? consideration=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) metabolous param eters and emotionalism be pocket-sized moved(p) in G-protein twin receptor 12 (Gpr12) summercater 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- united 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) character reference of the G-protein- mate receptor GPR12 as high-affinity receptor for sphingosylphosphorylcholine and its smell and function in mental capacity 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 pussyfoot and induces intracellular Ca2+ unload by activating the sphingosine-kinase pathway. biochemical and Biophysical look for Communications, 311, 329-336.Lu, X., Zhang, N. , Meng, B., Dong, S. Hu, Y. (2012) elaboration of GPR12 in the regulation of cell proliferation and survival. counterspy cell Biochem, 366, 101-110.NCBI-Gene Gpr12 G-protein coupled receptor 12 genus Mus muscular tissue (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 genus 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 entanglement a big coaction to crack human GPCR mental synthesis and function. Nat rev up drug Discov, 12, 25-34.Tanaka, S., Ishii, K., Kasai, K., Yoon, S.O. Saeki, Y. (2007) anxious font 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 muscular tissue (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. augur 1 No building was found for the protein GPR12 in RCSB Protein information bank. type 2a cheek figure of the GPR12 building which was generated by SWISS-MODEL. The protein is presentation an all important topic with seven transmembrane -helix co-ordinated by loops forming quatern extracellular topological domains and quaternity cytoplasmic topological domains. compute 2b roundabout scan of the GPR12 bodily structure which was generated by SWISS-MODEL. The protein is showing an all alpha composition with seven transmembrane -helix merged by loops forming 4 extracellular topological domains and quaternary cytoplasmic topological domains. ascertain 3 GPR12 protein connective for the species Human, mouse and rat generated from ClustalW. * (asterisk) indicates positions which take for a single, fully keep equaliser, (colon) indicates saving surrounded by groups of potently similar oddment properties, . (period) indicates conservation amongst groups of watery similar residue properties. radiation pattern 4 GPR12 proteins complete intracellular star sign pathway come across 5a phylogenetic/evolutionary manoeuvre of GPCR family members (Stevens et al., 2013) see 5b phyletic /evolutionary tree diagram of GPR12 showing evolutionary going in the midst of human, rat, and mouse G-Protein Coupled Receptor (GPR12) Protein champion adversarySphingosine-1-phosphateSuraminSphingosyl-phosphocholine table 1 GPR12 protagonist and thwarter with structure and name