Biomedical subjects

Q Liu

Publications and source records attributed to Q Liu.

At least 109 records · Page 6Linked to original sources

PubMed2001

Equilibrium and kinetics of bromine chloride hydrolysis.

Aqueous-phase halogen reactions play an important role in tropospheric ozone depletion that is observed during Arctic sunrise where bromine chloride is a key intermediate. The temperature dependencies of BrCl(aq) equilibration with BrCl2-, HOBr(aq), Br2(aq), Cl2(aq), HOCl(aq), Br-, and other species (Br3-, Br2Cl-, Cl3-, OBr-, and OCI-) are determined as a function of Cl- concentration from pH 0 to pH 7. Values for K1 (=[BrCl2-]/([BrCl(aq)][Cl-])) at mu = 1.0 M are 3.8 M(-1) at 25.0 degrees C, 4.7 M(-1) at 10.0 degrees C, and 5.5 M(-1) at 0.0 degrees C, with deltaH1 degrees = -9.9 kJ mol(-1) and deltaS1 degrees = -22 J K(-1) mol(-1). BrCl(aq) hydrolysis equilibria have little or no temperature dependence with Kh1 (=[HOBr(aq)][Cl-][H+]/[BrCl(aq)]) = 1.3 x 10(-4) M2 from 25.0 to 5.0 degrees C, mu = 1.0 M. When conditions are adjusted to give a rapid partial hydrolysis of BrCl in equilibrium with HOBr and Cl- at p[H+] 4.31, a relatively slow reaction (kobsd = 2.4 s(-1)) to form HOCl and Br- is observed. This takes place via BrCl reaction with Cl- to form Cl2, which hydrolyzes in the rate-determining step to give HOCl. On the other hand, the rate of complete BrCl hydrolysis to form HOBr and Cl- at p[H+] 6.4 is extremely rapid with a first-order rate constant of 3.0 x 10(6) s(-1) at 25.0 degrees C. The reverse reaction between HOBr, Cl-, and H+ has a rate constant of 2.3 x 10(10) M(-2) s(-1), so that in seawater, where [Cl-]/[Br-] = 700, the formation of BrCl is much faster than the formation of Br2 from HOBr, Br-, and H+. Rapid formation of BrCl(aq) and its subsequent reaction with Br- is a viable pathway to give Br2(aq). Photolysis of Br2(g) is believed to initiate the reactions associated with ozone depletion.

Bromides↗

PubMed2001

Mouse phosphoglycerate mutase M and B isozymes: cDNA cloning, enzyme activity assay and mapping.

Two mouse cDNAs encoding the non-muscle-specific or brain isoform (type B, Pgam1) and the muscle-specific isoform (type M, Pgam2) of phosphoglycerate mutase (PGAM) were isolated and characterized. Pgam1 contains a 765 bp open reading frame (ORF) coding for a 254-residue protein while Pgam2 contains a 762 bp ORF coding for a 253-residue protein. The deduced proteins of mouse Pgam1 and Pgam2 are highly similar to those of human and rat (> or = 93% similarity). Northern blot analysis showed that the expression patterns of Pgam1 and Pgam2 were distinct. Pgam1 was expressed as a 2.1-kb transcript highly in brain and kidney and moderately in liver, thyroid, stomach and heart, whereas Pgam2 was expressed as a 1.0-kb transcript highly in muscle, testis and moderately in heart and lung, but was not detectable in the other six tissues examined. Transfecting the cDNA fragments containing the entire ORFs of these two cDNAs into COS7 cells for transient expression, respectively, the enzyme activities of mouse Pgam1 and Pgam2 were detected to be 2.2-2.5 times of those of COS7 cells and COS7 cells transfected with vector, proving the validity of mouse Pgam1 and Pgam2 cDNAs we report here. Pgam1 and Pgam2 were assigned to 116.16 cR from D19Mit52 and 29.57 cR from D11Mit129, respectively, by radiation hybrid method. The partial genomic sequence of Pgam2 was determined, which showed that mouse Pgam2 consisted at least three exons and two introns. In addition, a pseudogene of Pgam1, Pgam1-ps1, was identified from mouse genomic sequence.

Amino Acid Sequence↗

PubMed2001

Engineering of a mammalian cell line for reduction of lactate formation and high monoclonal antibody production.

Lactate and ammonia are the two major waste products formed during mammalian cell growth. Accumulation of these side products can have a negative effect on cell growth, and has drawn recent attention because of their inhibitory effects on the specific product synthesis rate. Our aim is to reduce lactate formation in the cell culture by genetically manipulating of the pathway of lactate synthesis with an aim to achieve high monoclonal antibody production. We have partially disrupted the LDH-A gene by homologous recombination in hybridoma cells (ATCC-CRL-1606). The cells that received the newly introduced DNA were selected by G418, and an LDH-deficient cell was identified by a screening method based on medium color changing in 96-well plates. A variant cell, LDH-neo21, was identified through this screening method and was characterized. The specific productivity of lactate by LDH-neo21 cells was 50% lower than that of parental cells. Intracellular LDH enzyme activity was significantly reduced. The cell growth was improved both in terms of cell density and cell viability. Total cell density potentially reached 5 x 10(6) cells/mL while the parental hybridoma cells had a cell density of 3.5 x 10(6) cells/mL, which represented a 30% increase. The antibody production of LDH-neo21 cells was threefold greater than that of parental cells during 5-day batch culture. Polymerase chain reaction (PCR) results showed that at least one copy of the LDH-A gene was disrupted in the LDH-neo21 cells. The variant of the hybridoma cell exhibited a significant advantage of reduced lactate formation in the cell culture with a high concentration of glucose, which led to a higher production of monoclonal antibody. 2001 John Wiley & Sons, Inc.

Ammonia↗

PubMed2001

Regulation of an endogenous locus using a panel of designed zinc finger proteins targeted to accessible chromatin regions. Activation of vascular endothelial growth factor A.

We have mapped conserved regions of enhanced DNase I accessibility within the endogenous chromosomal locus of vascular endothelial growth factor A (VEGF-A). Synthetic zinc finger protein (ZFP) transcription factors were designed to target DNA sequences contained within the DNase I-hypersensitive regions. These ZFPs, when fused to either VP16 or p65 transcriptional activation domains, were able to activate expression of the VEGF-A gene as assayed by mRNA accumulation and VEGF-A protein secretion through a range exceeding that induced by hypoxic stress. Importantly, multiple splice variants of VEGF-A mRNA with defined physiological functions were induced by a single engineered ZFP transcription factor. We present evidence for an enhanced activation of VEGF-A gene transcription by ZFP transcription factors fused to VP16 and p65 targeted to two distinct chromosomal sites >500 base pairs upstream or downstream of the transcription start site. Our strategy provides a novel approach for dissecting the requirements for gene regulation at a distance without altering the DNA sequence of the endogenous target locus.

Cell Line, Transformed↗

PubMed2001

Synthesis and biological evaluation of novel pyrazoles and indazoles as activators of the nitric oxide receptor, soluble guanylate cyclase.

Database searching and compound screening identified 1-benzyl-3-(3-dimethylaminopropyloxy)indazole (benzydamine, 3) as a potent activator of the nitric oxide receptor, soluble guanylate cyclase. A comprehensive structure-activity relationship study surrounding 3 clearly showed that the indazole C-3 dimethylaminopropyloxy substituent was critical for enzyme activity. However replacement of the indazole ring of 3 by appropriately substituted pyrazoles maintained enzyme activity. Compounds were evaluated for inhibition of platelet aggregation and showed a general lipophilicity requirement. Aryl-substituted pyrazoles 32, 34, and 43 demonstrated potent activation of soluble guanylate cyclase and potent inhibition of platelet aggregation. Pharmacokinetic studies in rats showed that compound 32 exhibits modest oral bioavailability (12%). Furthermore 32 has an excellent selectivity profile notably showing no significant inhibition of phosphodiesterases or nitric oxide synthases.

Animals↗

PubMed2001

Exclusion of growth factor gene mutations as a common cause of Sotos syndrome.

Sotos syndrome is characterized by somatic overgrowth, i.e., macrocephaly and tall stature. Because the cause and pathogenesis of Sotos syndrome remain unknown, we selected nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3) as possible genes mutated in Sotos syndrome. In seven patients with the classic phenotype, we excluded mutations in these growth factor genes. It is possible that these three genes are not involved in the cause of Sotos syndrome, or alternatively, mutations could not be identified in the small number of patients studied.

Abnormalities, Multiple↗

PubMed2001

Zebrafish E-cadherin: expression during early embryogenesis and regulation during brain development.

Zebrafish E-cadherin (cdh1) cell adhesion molecule cDNAs were cloned. We investigated spatial and temporal expression of cdh1 during early embryogenesis. Expression was observed in blastomeres, the anterior mesoderm during gastrulation, and developing epithelial structures. In the developing nervous system, cdh1 was detected at the pharyngula stage (24 hpf) in the midbrain-hindbrain boundary (MHB). Developmental regulation of MHB formation involves wnt1 and pax2.1. wnt1 expression preceded cdh1 expression during MHB formation, and cdh1 expression in the MHB was dependent on normal development of this structure.

Animals↗

PubMed2001

Loss of chromosome arms 3p and 9p and inactivation of P16 (INK4a) in normal epithelium of patients with primary lung cancer.

The accumulation of genetic alterations in the respiratory epithelium may give rise to cancer and often is accompanied by a series of histologic alterations over a period of several years. Recent studies have identified some molecular alterations in histologically normal-appearing epithelium among patients with lung cancer. To extend these observations, we investigated clonal genetic alterations by using fluorescence in situ hybridization (FISH) analysis and immunohistochemistry in 69 biopsy samples of histologically normal-appearing bronchial epithelium from 22 patients with or without lung cancer. Thirty-seven biopsy specimens from 13 patients were examined for loss of 3p14, and 48 biopsy specimens from 18 patients were examined for loss at 9p21 by FISH. P16(INK4a) expression was analyzed in 54 biopsy samples from 19 patients. In at least one biopsy specimen from five of the 13 patients with primary lung cancer, FISH or immunohistochemistry detected loss of the 3p14 or 9p21 region. In contrast, no alterations were detected for the same regions in the nine patients without primary lung cancer. Our results support the concept that the normal epithelial surface of large bronchi of patients with lung cancer has molecular changes suggestive of the outgrowth of numerous clonal foci.

Bronchi↗

PubMed2001

Role of the oncogenic Raf-1 in orchestration of discrete nuclear factor-kappaB-activating pathways.

Raf-1, a key kinase in the Ras signaling pathway, plays critical roles in cell differentiation, proliferation, and tumorigenesis. However, knowledge of the Raf-1 in inflammation is limited. Using an inducible oncogenic Raf-1, we show that the Raf-1 orchestrates the discrete NF-kappaB activating pathways. While the Raf-1 activation induces a modest IkappaB degradation by enhancing the basal IkappaB kinase activity, it contradictorily suppresses the proinflammatory cytokine inducible IkappaB kinase complex, leading to an inhibition of TNF-alpha- and IL-1beta-induced NF-kappaB activation. Despite considerable degrees of overlap, LPS signaling is not affected by Raf-1. By either conditionally reducing Raf-1 activity or completely disrupting the Raf-1 signaling by PD98059, a specific inhibitor of MEK1, the otherwise inhibited cytokine responses can be restored. Moreover, when the activity of Raf-1 is up-regulated during the cell cycle progression from the G(0) phase to the late G(1) phase, the enhanced Raf-1 activity suffices to shift the TNF-alpha response from the sensitive to the insensitive state. Together, these studies elucidate a mechanism by which signaling outputs are shaped by the intracellular Raf-1, thus explaining the "cellular context"-dependent cytokine response.

Animals↗

PubMed2001

Bacterial expression of an immunologically reactive PCV2 ORF2 fusion protein.

The entire coding region of open reading frame 2 (ORF2) of porcine circovirus 2 (PCV2) was linked to the 3'-end of the maltose-binding protein (MBP)-His(8)-tag gene. The fusion protein was expressed as soluble form after induction by isopropylthio-beta-d-galactoside. MBP-His(8)-ORF2 was purified to homogeneity by immobilized metal affinity chromatography based on the interaction of the polyhistidine-tag with metal ions. Expression could represent 1% of the total protein in Escherichia coli, allowing approximately 1 mg of highly purified protein to be obtained per liter of bacterial culture. The fusion protein was recognized in Western blot by anti-PCV2 polyclonal antibody and swine sera with PCV2 infection. In addition, rabbit polyclonal antibody raised against purified MBP-His(8)-ORF2 fusion protein reacted with the ORF2 protein in immunoprecipitation. The availability of this fusion protein should permit a thorough study of prevalence of PCV2 infection in large-scale serological studies of field samples.

ATP-Binding Cassette Transporters↗

PubMed2001

The mechanical study of vascular endothelial growth factor on the prevention of restenosis after angioplasty.

The mechanism of vascular endothelial growth factor (VEGF) on the prevention of restenosis after angioplasty was investigated. The cultured vascular endothelial cells (VEC) were incubated with the conditioned medium (CM) from vascular smooth muscle cells (VSMC) infected with recombinant adenoviruses containing the hVEGF165 gene. To observe the effects of VEGF on proliferation and NO, ET, 6-keto-PGF1 alpha secretion of VEC, WST-1 method, Griess method and radioimmunoassay were used respectively. The PDGF-B mRNA transcription in VECs was detected by RT-PCR. It was showed that NO, 6-keto-PGF1 alpha and OD value were markedly increased in a dose-dependent manner in the VEGF-treated groups as compared with those in the control group, while ET and PDGF-B mRNA were significantly decreased in the VEGF-treated groups (P < 0.05 or P < 0.01). Adenovirus vector mediated hVEGF165 gene could promote the proliferation of VECs and improve NO, PGI2 secretion, inhibit ET secretion and PDGF-B mRNA transcription in the VECs. The above results offered further theoretical evidence for VEGF on the prevention of restenosis after angioplasty.

6-Ketoprostaglandin F1 alpha↗

PubMed2001

Nasal CD56 positive small round cell tumors. Differential diagnosis of hematological, neurogenic, and myogenic neoplasms.

CD56-positive nasal and nasal-type natural killer (NK)/T-cell lymphoma is now a well-defined disease entity. Rare cases of blastic NK-cell lymphoma positive for CD56 have been recently reported. However, CD56 expression is also identified in several types of non-hematopoietic small round cell tumors in which lymphoma is included as a differential consideration. Here, we present nine cases of CD56+ small round cell tumors of histological origin unrelated to nasal NK/T-cell lymphoma. Eight of the nine cases presented as solid tumors of the sinonasal region. Clinical, histological, ultrastructural, and immunohistochemical examination and gene analysis for T-cell receptor (TcR) and immunoglobulin heavy chain (IgH) genes and in situ hybridization (ISH) for Epstein-Barr virus (EBV) were performed. Two cases presented with features consistent with blastic NK-cell lymphoma or lymphoblastic lymphoma of NK-cell phenotype. These cases showed features of lymphoblastic lymphoma, phenotypes of sCD3-, cCD3+, CD45+, CD56+, TdT+, and human leukocyte antigen (HLA)-DR+, germline of IgH and TcR genes, and EBV negative reactivity. One case had myeloid/NK-precursor acute leukemia/lymphoma with a phenotype of CD13+, CD33+, CD34+, CD56+, and MPO-. Three cases were neurogenic, including one case of olfactory neuroblastoma and two of primitive neuroectodermal tumors (PNET). It was difficult to differentiate CD56+ PNET from blastic NK-cell lymphoma, especially when only paraffin-embedded sections were available. Myogenic markers, such as HHF35, alpha-sarcomeric actin, and desmin, were positive in three cases of rhabdomyosarcomas. Our findings suggest that as CD56 is used more routinely as a marker in immunohistochemical staining, the differential diagnosis of extranodal lymphohematological malignancies and small round cell tumors will become more complicated.

Adolescent↗

PubMed2001

Ecabet sodium inhibits the ability of Helicobacter pylori to induce neutrophil production of reactive oxygen species and interleukin-8.

The pathogenic role of human neutrophils has been implicated in Helicobacter pylori-associated gastritis. Ecabet sodium, a locally acting antiulcer drug, has anti-H. pylori actions. The aim of this study was to examine the effects of ecabet on the ability of H. pylori to stimulate human neutrophils. H. pylori were added to 1 x 10(5) neutrophils and incubated for 30 min in the presence of ecabet. Bacterial suspensions which had been incubated with ecabet for 30 min were also used to stimulate neutrophils. The intracellular production of reactive oxygen species was measured with a FACScan. Bacterial suspensions were also added to neutrophils in the presence of ecabet and incubated at 37 degrees C for 12 h to measure interleukin (IL)-8 production by enzyme-linked immunosorbent assay. The mean fluorescence intensity was found to be attenuated dose-dependently by ecabet (P < 0.01). Ecabet also inhibited IL-8 production by neutrophils in a dose-dependent manner (P < 0.001). Bacteria with prior incubation with ecabet induced significantly lower IL-8 production than those without this incubation (P < 0.05). Ecabet sodium has preventive effects on the ability of H. pylori to stimulate human neutrophils. It may lead to reduced gastritis activity and decreased oxidative damage of the gastric mucosa in H. pylori-associated gastritis.

Abietanes↗

PubMed2001

Identification of apoptosis-inhibiting gene in Leucania separata nuclear polyhedrosis virus.

A novel gene lsp40 from leucania separata nuclear polyhedrosis virus (LsNPV) which was homologous to the p35 gene from Autographa californica Nuclear Polyhedrosis Virus (AcNPV) was localized in the EcoRV-5.5 kb fragment of LsNPV genome DNA and was sequenced. The open reading frame (ORF) of lsp40 was 906 bp long and encoded an approximately 40 kDa peptide consisting of 302 amino acid residues. The Isp40 shares 80.4% and 70.4% identity of nucleotide and amino acid sequence, respectively, to the AcNPV-p35 gene. The identity in promoters of both genes was as high as 100%. It was found that there were two TATA and GC boxes, three ACGT motifs for initiation of early gene transcription and one typical TTAAG core sequence for initiation of late gene transcription at both gene's 5' end, and two AATAAA tail signals at 3' end. The Isp40 started to express 2 hours after being transfected into the Ls cells to produce an approximately 40 kDa protein. The expression of the lsp40 gene might also inhibit the apoptosis of the Ls cells induced by removing serum. The expression of lsp40 in Vero cells delayed the apoptosis of the Vero cells induced by poliovirus infection. The lsp40 gene rescued vAcAnh (a kind of AcNPV p35-deletion mutant) in the Sf9 cells resulting in inhibition of the apoptosis and production of polyhedra. All these data suggested that the lsp40 gene was a homologous and functional gene similar to AcNPV p35 gene.

Amino Acid Sequence↗

PubMed2001

The effect of glucagon-like peptide 2 on intestinal permeability and bacterial translocation in acute necrotizing pancreatitis.

BACKGROUND: Acute pancreatitis (AP) initiates a generalized inflammatory response that increases intestinal permeability and promotes bacterial translocation (BT). Impairment of the intestinal epithelial barrier is known to promote BT. Glucagon-like peptide 2 (GLP-2), a 33 residue peptide hormone, is a key regulator of the intestinal mucosa by stimulating epithelial growth. The purpose of this study was to determine whether GLP-2 decreases intestinal permeability and BT in AP. METHODS: To examine whether GLP-2 can decrease intestinal permeability and thereby decrease BT in acute necrotizing pancreatitis, 34 male Sprague-Dawley rats (200 to 300 g) were studied. AP was induced in group I and group II by pressure injection of 3% taurocholate and trypsin into the common biliopancreatic duct (1 mg/kg of body weight). The potent analog to GLP-2 called ALX-0600 was utilized. Group I rats received GLP-2 analog (0.1 mg/kg, SQ, BID) and group II rats received a similar volume of normal saline as a placebo postoperatively for 3 days. Group III and group IV received GLP-2 analog and placebo, respectively. At 72 hours postoperatively, blood was drawn for culture of gram-negative organisms. Specimens from mesenteric lymph nodes (MLN), pancreas and peritoneum were harvested for culture of gram-negative bacteria. Intestinal resistance as defined by Ohm's law was determined using a modified Ussing chamber to measure transepithelial current at a fixed voltage. A point scoring system for five histologic features that include intestinal edema, inflammatory cellular infiltration, fat necrosis, parenchymal necrosis, and hemorrhage was used to evaluate the severity of pancreatitis. Specimens from MLN, pancreas, jejunum, and ileum were taken for pathology. RESULTS: All group I and group II rats had AP. The average transepithelial resistance in group I was 82.8 Omega/cm(2) compared with 55.9 Omega/cm(2) in group II (P <0.01). Gram-negative BT to MLN, pancreas, and peritoneum was 80%, 0%, and 0%, respectively in group I compared with 100%, 30%, and 20% translocation in group II. CONCLUSION: GLP-2 treatment significantly decreases intestinal permeability in acute pancreatitis.

Analysis of Variance↗

PubMed2001

Lipoprotein lipase D9N, N291S and S447X polymorphisms: their influence on premature coronary heart disease and plasma lipids.

Lipoprotein lipase (LPL) plays a pivotal role in lipoprotein metabolism. Three recently described exonic polymorphisms of the gene, D9N, N291S and S447X, have been variably found to influence plasma lipids while effects on coronary heart disease (CHD) are less well documented. Two predominantly Caucasian groups were studied: CHD patients <50 years of age, with angiographically documented CHD; and a randomly recruited community control group without a history of heart disease. The 9N allele of the D9N polymorphism was present in 25 of 428 (5.8%) of Caucasian males with CHD and in seven of 291 (2.4%) of corresponding community subjects (odds ratio, 2.5; 95% confidence interval (CI), 1.1-5.9; P=0.03) and was also significantly over-represented in the Caucasian males with myocardial infarction (MI) (21 of 308 or 6.8%; odds ratio, 2.6; 95% CI, 1.1-5.9; P=0.01). The distributions of the other two polymorphisms were similar in the CHD and community groups. In multivariate models adjusted for age, sex, diabetes, body mass index, smoking, lipid levels and race, the D9N polymorphism remained significantly related to both CHD and MI, with an odds ratio >2. There were, generally, trends to more adverse fasting plasma high-density lipoprotein (HDL) cholesterol and triglycerides in carriers of the 291S and 9N alleles, and the opposite trends for triglycerides in 447X carriers. In the community group, male carriers of 291S (n=13) had significantly (20%) lower HDL cholesterol than corresponding non-carriers (n=323), 0.98+/-0.07 mmol/l (mean+/-S.E.) versus 1.22+/-0.02 mmol/l (P<0.005), while HDL cholesterol was not different in male carriers (n=8) and non-carriers (n=296) of 9N (1.23+/-0.13 mmol/l versus 1.22+/-0.02 mmol/l). Multivariate analysis confirmed that the 291S allele carrier status conferred a significantly lower HDL cholesterol (P=0.001) and the 447X allele lower triglyceride (P<0.01) in the community group. In conclusion, LPL 9N carrier status was unequivocally related to premature CHD and to MI in males, strongly supporting recent results in older aged males. The somewhat different effects of the D9N and N291S polymorphisms on plasma lipids, and the absence of a clear effect of the N291S on CHD, raise the possibility that the effect of 9N carrier status might be mediated through effects on LPL function in addition to those influencing fasting plasma lipids.

Adult↗

PubMed2001

Binding of anticoagulation factor II from the venom of Agkistrodon acutus with activated coagulation factor X.

Anticoagulation factor II (ACF II) from the venom of Agkistrodon acutus has been identified as a binding protein to activated bovine coagulation factor X (FXa) by the method of polyacrylamide gel electrophoresis and high performance liquid chromatography. This protein formed a 1:1 complex with FXa in the presence of Ca2+ ions, and the maximal binding of ACF II to FXa occurred at the concentration of Ca2+ ions of about 1mM. The binding of Ca2+ ions to ACF II was analyzed by equilibrium dialysis and two Ca2+-binding sites with different affinities were identified. At pH 8.0, the apparent association constant K1 and K2 values for these sites were (1.1+/-0.3)x10(5) M(-1) and (1.7+/-0.4)x10(4) M(-1) (mean+/-SE, n=4), respectively. It was evident from the observation of Ca2+-induced changes in the intrinsic fluorescence of ACF II that ACF II underwent a conformational change upon binding of Ca2+ ions. The occupation of both Ca2+-binding sites in ACF II requires a concentration of Ca2+ ions of about 1mM, which is equal to the effective concentration of Ca2+ ions required for maximal binding of ACF II to FXa, and for the maximal Ca2+-induced enhancement of emission fluorescence of ACF II. It can be deduced from these results that the occupation of both Ca2+-binding sites in ACF II with Ca2+ ions and subsequent conformational rearrangement should be essential for its recognition of Ca2+-mediated conformational changes of FXa.

Agkistrodon↗

PubMed2001

Orphan G-protein-coupled receptors and natural ligand discovery.

The superfamily of seven-transmembrane-domain G-protein-coupled receptors (GPCRs) is the largest and most diverse group of transmembrane proteins involved in signal transduction. Each of the approximately 1000 family members found in vertebrates responds to stimuli as diverse as hormones, neurotransmitters, odorants and light, which selectively activate intracellular signaling events mediated by heterotrimeric G proteins. Because GPCRs are centrally positioned in the plasma membrane to initiate a cascade of cellular responses by diverse extracellular mediators, it is not surprising that modulation of GPCR function has been successful in the development of many marketed therapeutic agents. It has become clear that GPCRs for which a natural activating ligand has not yet been identified (orphan GPCRs) might provide a path to discovering new cellular substances that are important in human physiology. The process of 'de-orphanizing' these novel proteins has accelerated significantly and opened up new avenues for research in human physiology and pharmacology.

Animals↗