Disease relevance of CYSLTR2

• A strain with targeted disruption of the CysLT1 receptor gene is protected against the pathobiological insults that augment microvascular permeability, whereas a strain with targeted disruption of the CysLT2 receptor gene is protected against pulmonary fibrosis [1].
• Because RSK2-inactivating mutations in humans lead to Coffin-Lowry syndrome, our results imply that alterations in GPCR signaling may account for some of its clinical manifestations [2].
• Together, our results demonstrate the importance of a mechanism that promotes head and neck cancer cell proliferation and motility by GPCR ligands involving EGFR transactivation [3].
• In a variety of squamous cell carcinoma cell lines of the head and neck (HNSCCs), we found that treatment with the GPCR agonists lysophosphatidic acid (LPA), bradykinin, thrombin, and carbachol results in rapid tyrosine phosphorylation of the EGFR [3].
• Because charged residues at the intracellular ends of transmembrane helix (TMH) 2 and TMH3 of G protein-coupled receptors (GPCRs) affect signaling, we performed mutational analysis of these residues in the constitutively signaling Kaposi's sarcoma-associated herpesvirus GPCR (KSHV-GPCR) [4].

Psychiatry related information on CYSLTR2

• Many drugs of abuse signal through receptors that couple to G proteins (GPCRs), so the factors that control GPCR signaling are likely to be important to the understanding of drug abuse [5].
• Given the complexity of neurological disorders such as ischemic stroke, Alzheimer's disease and epilepsy, exploitation mGlu receptor-associated GPCR interactions may prove efficacious in the treatment of such disorders [6].

High impact information on CYSLTR2

• Future high-resolution structural studies of rhodopsin and other GPCRs will form a basis to elucidate the detailed molecular mechanism of GPCR-mediated signal transduction [7].
• Significantly, GPCR-containing CCPs are also functionally distinct, as their surface residence time is regulated locally by GPCR cargo via PDZ-dependent linkage to the actin cytoskeleton [8].
• Our results reveal a novel function of betaarr1 as a cytoplasm-nucleus messenger in GPCR signaling and elucidate an epigenetic mechanism for direct GPCR signaling from cell membrane to the nucleus through signal-dependent histone modification [9].
• A nuclear function of beta-arrestin1 in GPCR signaling: regulation of histone acetylation and gene transcription [9].
• Our data suggest that OA1 represents the first example of an exclusively intracellular GPCR and support the hypothesis that GPCR-mediated signal transduction systems also operate at the internal membranes in mammalian cells [10].

Chemical compound and disease context of CYSLTR2

• In PC12 rat pheochromocytoma cells, both agents block lysophosphatidic acid (LPA)- and bradykinin-stimulated Erk 1/2 phosphorylation, suggesting that intact focal adhesion complexes are required for GPCR-induced mitogen-activated protein kinase activation in these cells [11].
• Here we report that a synthetic peptide derived from the NH2-terminal extracellular region of an orphan GPCR, GPR1 (GPR1ntP-(1-27); MEDLEETLFEEFENYSYDLDYYSLESC), inhibited infection of not only an HIV-1 variant that uses GPR1 as a co-receptor, but also X4, R5, and R5X4 viruses [12].

Biological context of CYSLTR2

• METHODS: The association of CYSLTR2 polymorphisms with asthma was assessed by transmission disequilibrium test in two family-based collections (359 families from Denmark and Minnesota, USA and 384 families from the Genetics of Asthma International Network) [13].
• We characterized the genomic structure of humans CYSLTR2, determined the putative major promoter region and conducted association studies pertaining to polymorphisms in CYSLTR2 and asthma [14].
• OBJECTIVE: Cysteinyl leukotriene receptor 2 (CYSLTR2) is one of the receptors for the cysteinyl leukotrienes (CYSLTs), which cause bronchoconstrictions, vascular hyperpermeability and mucus hypersecretion in asthmatic patients [14].
• METHODS AND RESULTS: We identified three novel exons in the 5' untranslated region of CYSLTR2 by rapid amplification of cDNA ends and identified eight novel polymorphisms in CYSLTR2 by direct sequencing [14].
• METHODS: Gene expression of CysLTR1 and CysLTR2 mRNAs in human peripheral blood eosinophils, neutrophils, monocytes and T lymphocytes has been measured by competitive reverse transcription-polymerase chain reactions using RNA or DNA competitors [15].

Anatomical context of CYSLTR2

• The ratio of CysLTR1 mRNA to CysLTR2 mRNA was significantly lower in eosinophils (0.65 +/- 0.42, n = 12) than in neutrophils (6.9 +/- 4.9, n = 12), monocytes (1.8 +/- 0.9, n = 10) and T lymphocytes (4.5 +/- 5.7, n = 10) [15].
• (c) Human umbilical vein endothelial cells expressed CysLTR2 mRNA, but not CysLTR1 mRNA [15].
• Levels of cysteinyl leukotriene receptor mRNA in human peripheral leucocytes: significantly higher expression of cysteinyl leukotriene receptor 2 mRNA in eosinophils [15].
• Total RNA was isolated from human nasal mucosa and both CysLT1 and CysLT2 receptor mRNA was detected in these tissues by using RT-PCR [16].
• Large amounts of the PSEC0146 mRNA are found in human heart, placenta, spleen, and peripheral blood leukocytes but not in the lung and the trachea [17].

Associations of CYSLTR2 with chemical compounds

• CONCLUSIONS: Since 601A>G alters the potency of LTD4 and this variant allele may be associated with resistance to asthma, it is possible that modulation of the CYSLTR2 may be useful in asthma pharmacotherapy [13].
• The potency of LTC4 and LTE4 was similar for both forms of the receptor and LTB4 was inactive, however, LTD4 was approximately five-fold less potent on 601A>G compared to wild-type CYSLTR2 [13].
• To overcome the difficulty of characterizing the structures of the extracellular loops (eLPs) of G protein-coupled receptors (GPCRs) other than rhodopsin, we have explored a strategy to generate a three-dimensional structural model for a GPCR, the thromboxane A(2) receptor [18].
• The cysteinyl leukotrienes (cys-LTs), i.e. LTC(4), LTD(4) and LTE(4), trigger contractile and inflammatory processes through the specific interaction with cell surface receptors belonging to the purine receptor cluster of the rhodopsin family of the G protein-coupled receptor (GPCR) genes [19].
• We provide here structural evidence that the protein product of the ocular albinism type 1 gene (OA1), a pigment cell-specific integral membrane glycoprotein, represents a novel member of the GPCR superfamily and demonstrate that it binds heterotrimeric G proteins [10].
• This response was mediated by CysLTR2 coupled to G(q/11), activation of phospholipase C, and inositol-1,4,5-triphosphate, and was enhanced further 2- to 5-fold by IFN-gamma stimulation [20].

Other interactions of CYSLTR2

• BACKGROUND: Cysteinyl leukotrienes (CYSLTR) are potent biological mediators in the pathophysiology of asthma for which two receptors have been characterized, CYSLTR1 and CYSLTR2 [13].
• The novel M202V CysLT2 receptor variant was associated with atopy (21%) on Tristan da Cunha compared with those who were non-atopic (7%) (Fisher's exact test, P=0.0016) in a manner that was independent of asthma (two-way ANOVA, P=0.0015) [21].
• The former plays an important role in the control of cell growth that may serve as a prototypical G protein; the latter is a target for nitric oxide-mediated desensitization that may serve as a prototypical GPCR [22].

Analytical, diagnostic and therapeutic context of CYSLTR2

• RESULTS: RT-PCR analysis of total nasal RNA demonstrated the expression of both CysLT1 receptor and CysLT2 receptor mRNA [16].
• OBJECTIVE: We have used reverse transcription and polymerase chain reaction (RT-PCR) to study the gene expression of CysLT1 and CysLT2 receptor and in situ hybridization to determine the distribution of CysLT1 receptor mRNA in human nasal mucosa [16].
• Graded reductions in GPCR expression can be achieved through antisense strategies or total gene ablation or replacement can be achieved through gene targeting strategies, and exogenous expression of wild-type or mutant GPCR isoforms can be accomplished with transgenic technologies [23].
• Using a degenerate PCR approach, we have identified 15 G protein-coupled receptors (GPCR) from human and rodent tissues [24].
• In the present study we demonstrate the formation of an agonist-induced multimeric complex containing a GPCR, betaarrestin 2, and the beta2-adaptin subunit of AP-2. beta2-Adaptin binds betaarrestin 2 in a yeast two-hybrid assay and coimmunoprecipitates with betaarrestins and beta2AR in an agonist-dependent manner in HEK-293 cells [25].

References