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At least 1,693 records · Page 94Linked to original sources
PubMed1998

Identification of a unique ligand which has high affinity for all four bombesin receptor subtypes.

Four subtypes of bombesin receptors are identified (gastrin-releasing peptide receptor, neuromedin B receptor, the orphan receptor bombesin receptor subtype 3 (BB3 or BRS-3) and bombesin receptor subtype 4 (BB4)), however, only the pharmacology of the gastrin-releasing peptide receptor has been well studied. This lack of data is due in part to the absence of a general ligand. Recently we have discovered a ligand, 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) that binds to BRS-3 receptors. In this study we investigate its ability to interact with all four bombesin receptor subtypes. In rat pancreatic acini containing only gastrin-releasing peptide receptor and in BB4 transfected BALB cells, this ligand and 125I-[Tyr4]bombesin, the conventional gastrin-releasing peptide receptor ligand, gave similar results for receptor number, affinity for bombesin and affinity for the unlabeled ligand. In neuromedin B receptor transfected BALB cells, this ligand and 125I-[D-Tyr0]neuromedin B, the generally used neuromedin B receptor ligand, gave similar results for receptor number, neuromedin B affinity or the unlabeled ligand affinity. Lastly, in BRS-3 transfected BALB cells, only this ligand had high affinity. For all four bombesin receptors this ligand had an affinity of 1-8 nM and was equal or greater in affinity than any other specific ligands for any receptor. The unlabeled ligand is specific for gastrin-releasing peptide receptors on rat pancreatic acini and did not inhibit binding of 125I-cholecystokinin octapeptide (125I-CCK-8), 125I-vasoactive intestinal peptide (125I-VIP) or 125I-endothelin to their receptors. The unlabeled ligand was an agonist only at the gastrin-releasing peptide receptor in rat acini and did not interact with CCK(A) receptors or muscarinic M3 acetylcholine receptors to increase [3H]inositol phosphates. These results demonstrate 125I-[D-Tyr6,betaAla11,Phe13,Nle14]bombesin-(6-1 4) is a unique ligand with high affinity for all subtypes of bombesin receptors. Because of the specificity for bombesin receptors, this ligand will be a valuable addition for such pharmacological studies as screening for bombesin receptor agonists or antagonists and, in particular, for investigating BRS-3 cell biology, a receptor for which no ligand currently exists.

3T3 Cells↗
PubMed1999

Alpha1-adrenoceptor subtypes.

Alpha1-adrenoceptors are one of three subfamilies of receptors (alpha1, alpha2, beta) mediating responses to adrenaline and noradrenaline. Three alpha1-adrenoceptor subtypes are known (alpha1A, alpha1B, alpha1D) which are all members of the G protein coupled receptor family, and splice variants have been reported in the C-terminus of the alpha1A. They are expressed in many tissues, particularly smooth muscle where they mediate contraction. Certain subtype-selective agonists and antagonists are now available, and alpha1A-adrenoceptor selective antagonists are used to treat benign prostatic hypertrophy. All subtypes activate phospholipase C through the G(q/11) family of G proteins, release stored Ca2+, and activate protein kinase C, although with significant differences in coupling efficiency (alpha1A > alpha1B > alpha1D). Other second messenger pathways are also activated by these receptors, including Ca2+ influx, arachidonic acid release, and phospholipase D. Alpha1-adrenoceptors also activate mitogen-activated protein kinase pathways in many cells, and some of these responses are independent of Ca2+ and protein kinase C but involve small G proteins and tyrosine kinases. Direct interactions of alpha1-adrenoceptors with proteins other than G proteins have not yet been reported, however there is a consensus binding motif for the immediate early gene Homer in the C-terminal tail of the alpha1D subtype. Current research is focused on discovering new subtype-selective drugs, identifying non-traditional signaling pathways activated by these receptors, clarifying how multiple signals are integrated, and identifying proteins interacting directly with the receptors to influence their functions.

Adrenergic alpha-Agonists↗
PubMed1997

Coexistence of somatostatin receptor subtypes in the human neuroblastoma cell line LA-N-2.

Five distinct human somatostatin receptor subtypes have recently been cloned and characterized. Previous studies have suggested that these receptor subtypes might display coexistent localization, based on in situ hybridization or immunoblockage experiments. Here we provide evidence for coexistence of somatostatin receptor subtypes 2 and 5 in the human neuroblastoma cell line LA-N-2, using a combined approach with RT-PCR and receptor binding studies with somatostatin analogues. Somatostatin receptor subtypes simultaneously localized to a single cell might serve distinct functions in terms of targeting to different intraneuronal compartments or subtype specificity against so far unidentified somatostatin-related peptides.

Aged↗
PubMed1983

Mortality among children with rhabdomyosarcomas of the alveolar histologic subtype.

Of 116 patients with rhabdomyosarcoma of the alveolar histologic subtype who entered the Intergroup Rhabdomyosarcoma Study (IRS) from 1972 to 1978, there were 72 deaths (63%), compared with a mortality of 39% among patients with all nonalveolar types combined. The subgroup with alveolar histology contributed greater than 29% of the total mortality, although it represented 20% of the total patients (p less than .001). This recurrence rate reflects increased local, regional, and distant relapse. Differences were most marked in patients with grossly excised tumors (clinical groups I and II) in which the mortality was 44% in patients with alveolar tumors (48 patients) versus 13.5% in those with embryonal histology (111 patients), and 16% in all patients with nonalveolar tumor types. When survival was influenced by primary tumor site this reflected, in most body areas, an increase in the proportion of patients with the alveolar histology in that site. Patients with unresected or disseminated tumors (clinical groups III and IV) of the alveolar subtype have initial response rates to VAC and radiotherapy which are similar to those of patients with tumors of other cell subtypes (70% for group III and 50% for group IV). In these clinical groups, the differences in survival related to histologic subtype are not significant. The presence of the alveolar histologic subtype represents a rational basis for employing more intensive therapy in the management of patients with rhabdomyosarcomas.

Adolescent↗
PubMedDate not supplied

Identification of neuropsychological subtypes in a sample of delinquent adolescents.

Although research has long recognized a relationship between neurological dysfunction and delinquency, the nature of this relationship is unclear. Based on the theory that there may be clusters of delinquents with different types of neurological dysfunction which contribute to the delinquency in different ways, the present research attempted to identify these subtypes using neuropsychological testing. Seventy-seven such adolescents were administered the full Luria-Nebraska Neuropsychological Battery-III (LNNB-III) and a battery of assessments measuring behavioral functioning and substance use. A Hierarchical Cluster Analysis yielded four identifiable neuropsychological clusters: Verbal/Left-Hemispheric Deficits, Subcortical-Frontal Deficits, Mild-Verbal Deficits, and Normals. The distinctiveness of these subtypes was confirmed by univariate analyses. Results further indicated that the number of LNNB scales that were in the abnormal range differed per subtype, with each subtype differing significantly from one another. These neuropsychological subtypes were found to be associated with specific psychological and behavioral problems.

Adolescent↗
PubMed1997

Comparison of the Ca2+ movement by activation of alpha1-adrenoceptor subtypes in HEK-293 cells.

We studied the Ca2+ movement induced by activation of alpha1A-, alpha1B- and alpha1D-adrenoceptor subtypes in transfected HEK-293 cells with the fura-2 probe. All these alpha1-AR subtypes induced both Ca2+ release and Ca2+ entry. The effect on Ca2+ release in alpha1b transfected HEK-293 cells was bigger than that in alpha1a and alpha1d transfected HEK-293 cells, and the effects on Ca2+ entry were the same in alpha1a, alpha1b and alpha1d transfected HEK-293 cells. The Ca2+ entry was inhibited by 1 mM NiSO4, but not by nifedipine. Cyclopiazonic acid (CPA) produced a biphasic Ca2+ signal response in Ca2+ medium, and only induced a transient response in Ca2+-free medium. After depletion of CPA-sensitive Ca2+ pool by 10 microM CPA in Ca2+-free medium, 10 microM adrenaline (Adr) still transiently increased [Ca2+]i in three different alpha1-adrenoceptor subtype transfected HEK-293 cells. However, after depletion of adrenaline-sensitive Ca2+ pool by 10 microM Adr, CPA transiently elevated [Ca2+]i only in alpha1a and alpha1d transfected HEK-293 cells, not in alpha1b transfected HEK-293 cells. U73122, a phospholipase C (PLC) inhibitor, inhibited both Ca2+ release and Ca2+ entry induced by activation of alpha1A alpha1B and alpha1D subtypes in transfected HEK-293 cells. These results suggest that HEK-293 cell line contains two functionally separate intracellular Ca2+ pools, CPA-sensitive and Adr-sensitive pools. Activation of alpha1B-AR stimulates Ca2+ release from both CPA-sensitive and Adr-sensitive Ca2+ pools. Alpha1A and alpha1D subtypes induce Ca2+ release only from Adr-sensitive Ca2+ pool.

Animals↗
PubMed1998

Characterisation of subtypes of the P2X and P2Y families of ATP receptors in the foetal human heart.

ATP exerts a variety of actions within the myocardium, including the regulation of coronary vascular tone and modulation of the autonomic control of the heart. In order to characterise the ATP receptor subtypes involved in these effects, degenerate oligonucleotides were used to clone receptors of both P2X and P2Y families from the human foetal heart. About 1 ng of "Quick-Clone cDNA" from foetal human heart was subjected to amplification with two pairs of degenerate oligonucleotides designed to amplify subtypes of the P2X and P2Y receptor families by means of PCR reactions. The sequence analysis of 34 and 29 clones of the P2X and P2Y receptor families, respectively, demonstrated that P2X1, P2X3 and P2X4 subtypes are present in the human foetal heart together with P2Y6, P2Y2 and P2Y4 receptors. P2X1 and P2Y4 receptor subtypes were here characterised for the first time in the human foetal heart. The present study provides the first molecular characterisation of ATP receptors in the foetal human heart. The results show that many P2 receptor subtypes are expressed in the foetal human heart, perhaps contributing to developmental processes as well as to the activity of the foetal heart.

Amino Acid Sequence↗
PubMed1998

Subtype-specific differences in subcellular localization and chlorethylclonidine inactivation of alpha1-adrenoceptors.

Chlorethylclonidine (CEC) inactivation has been used as one criterion to subclassify the alpha1-adrenoceptors (AR); however, the extent of CEC inactivation can vary depending on the CEC treatment. By constructing the FLAG-tagged (N-terminus) and green fluorescent protein (GFP)-fused (C-terminus) alpha1-ARs, we have determined the relationship between CEC sensitivity and the cellular localization of alpha1-AR subtypes using COS-7 cells. In GFP-expressing cells, flow cytometry analysis with anti-FLAG N-terminus antibody detected strong fluorescent signals in most of alpha1B-AR-expressing cells, but low signals in alpha1A-AR-expressing cells. Further examination with confocal microscopy showed that fluorescent signals densely localized intra-cellularly in alpha1A-AR-expressing cells, while most of alpha1B-AR localized on the cell surface. Furthermore, radioligand binding studies with [125I]HEAT showed that CEC (10 microM) treatment of intact cells inactivated approximately 30-40% of alpha1A-AR and >90% of alpha1B-AR, while the CEC treatment of membrane preparations resulted in >80% decrease in the alpha1A-AR density and >90% of alpha1B-AR density, respectively. The results showed that the hydrophilic alkylating agent CEC inactivated only alpha1-AR on the cell surface irrespective of its subtype, and that the subtype-specific sorting is a major determinant for CEC inactivation of alpha1-AR. Subtype-specific cellular localization suggests a new class of functional properties that may explain the signal and functional diversity of homologous alpha1-AR (as well as other G protein-coupled receptors) subtypes.

Adrenergic alpha-Antagonists↗
PubMed1999

Muscarinic receptor subtypes involved in hippocampal circuits.

Muscarinic receptors modulate hippocampal activity in two main ways: inhibition of synaptic activity and enhancement of excitability of hippocampal cells. Due to the lack of pharmacological tools, it has not been possible to identify the individual receptor subtypes that mediate the specific physiological actions that underlie these forms of modulation. Light and electron microscopic immunocytochemistry using subtype-specific antibodies was combined with lesioning techniques to examine the pre- and postsynaptic location of m1-m4 mAChR at identified hippocampus synapses. The results revealed striking differences among the subtypes, and suggested different ways that the receptors modulate excitatory and inhibitory transmission in distinct circuits. Complementary physiological studies using m1-toxin investigated the modulatory effects of this subtype on excitatory transmission in more detail. The implications of these data for understanding the functional roles of these subtypes are discussed.

Animals↗
PubMed2001

Characterisation of [(125)I]-apamin binding sites in rat brain membranes with HE293 cells transfected with SK channel subtypes.

The pharmacology of [(125)I]-apamin binding sites was examined in rat cortical and hippocampal tissue and compared with membranes prepared from human embryonic kidney (HEK293) cells transfected with SK channel subtypes hSK1, rSK2 and rSK3. The K(D) of [(125)I]-apamin in rat cortex and hippocampus was similar to the apamin-sensitive subtypes, rSK2 and rSK3 (K(D) (pM): 6.4, 7.08, 6.56 and 8.94, respectively). In addition, [(125)I]-apamin had a K(D)=270.4pM for the putatively 'apamin-insensitive' hSK1. Apamin had about a three-fold higher affinity than [(125)I]-apamin in brain tissue and in the cells expressing the different SK channel subtypes. Pancuronium, bicuculline and d-tubocurarine displayed micromolar affinity for all five-membrane preparations, whereas dequalinium and gallamine appear to show some subtype selectivity. Tetraethylammonium (TEA) and 4-aminopyridine (4-AP) had millimolar affinity and linopirdine had no effect. In conclusion, the pharmacology of [(125)I]-apamin binding in the cortex and hippocampus was similar to that in the apamin-sensitive clones, rSK2 and rSK3. In addition, we demonstrated low affinity [(125)I]-apamin binding for hSK1 and identified compounds that show subtype selectivity. These data cast further doubt on the identification of SK1 as encoding for the K(+) channel responsible for the apamin-insensitive sAHP.

Animals↗
PubMed1994

HIV-1/HIV-2 seronegativity in HIV-1 subtype O infected patients.

Nine patients with atypical HIV-1 western blot profiles were diagnosed as having HIV-1 subtype O infection. All the patients were living in France; eight originated from Cameroon and one from France. Lymphocyte DNA amplification by the polymerase chain reaction was only positive when HIV-1 subtype O specific primers were used. Preliminary sequence analysis of amplified products and serological reactivity against a specific subtype O synthetic env peptide confirmed HIV-1 subtype O infection. HIV-1/HIV-2 enzyme-linked immunosorbent assays, especially those based on env peptides or on the sandwich format, can be negative in HIV-1 subtype O infection.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Types and subtypes of 73 strains of Haemophilus influenzae isolated from patients more than 6 years of age with meningitis in The Netherlands.

Strains of Haemophilus influenzae isolated in The Netherlands between 1975 and 1984 from patients with meningitis were analysed in order to determine whether older patients are infected with particular types or subtypes of the organism. Of 1154 patients with H. influenzae meningitis 73 (6.3%) were more than 6 years of age. Thirty-one strains (42%) were of serotype b, one strain was of serotyped, one strain was of serotype f and 40 strains (55%) were non-typable. Twenty-eight type b strains were available for subtyping by analysis of the major outer-membrane proteins by sodium dodecylsulphate (SDS)-polyacrylamide gel electrophoresis (PAGE), by serotyping of their lipopolysaccharides and by biotyping. Twenty-one strains were outer-membrane protein subtype 1,24-lipopolysaccharide serotype 1 and 24 biotype I. Seventeen strains (61%) combined these characteristics. This percentage did not differ significantly from the percentage found for strains isolated from patients of all age groups (80%). The 32 non-typable H. influenzae strains analysed had different outer-membrane protein patterns as seen by SDS-PAGE. Five biotypes were found, among which biotype II was predominant (21/32). The results indicated that (i) patients more than 6 years of age were infected by subtypes of H. influenzae b strains which were not significantly different from the strains isolated from younger patients, (ii) non-typable strains of H. influenzae were much more common (55%) in the older age group than in the younger (1.2%) and (iii) that these non-typable strains were not of a particular subtype.

Adolescent↗
PubMed1994

HBsAg subtypes among HBsAg carriers in Okinawa, Japan. Evidence of an important relationship in seroconversion from HBeAg to anti-HBe.

In Okinawa, Japan 1261 hepatitis B surface antigen (HBsAg) carriers were investigated for clinical differences among HBsAg subtypes. Among the 854 for whom they could be determined, subtype adw was found in 604 (70.7%), adr in 232 (27.2%) and others in 18 (2.1%). The overall prevalence of hepatitis B e antigen (HBeAg) was significantly lower in subtype adw (11.9%) than in adr (17.7%) (P < 0.01). The mean age of HBeAg-positive carriers was significantly lower in adw (20.4 years) than in adr (26.9 years) (P < 0.05). Seroconversion from HBeAg to antibody to HBeAg (anti-HBe) occurred in 43 carriers. The seroconversion rate was higher in adw (43.1%) than in adr (29.3%) and the seroconversion age was younger in adw (22.7 years) than in adr (27.9 years). These results suggest that carriers with subtype adw tend to seroconvert from HBeAg to anti-HBe at a higher rate and a younger age than do those with adr. HBsAg subtypes may be closely associated with the HBeAg/anti-HBe status.

Adolescent↗
PubMed1999

Relative amounts of mRNA encoding four subtypes of muscarinic receptors (m2-m5) in human peripheral blood mononuclear cells.

It is known that lymphocytes express functional muscarinic cholinergic receptors. In this study, RT-PCR method was applied to study the presence and relative levels of mRNA encoding muscarinic receptor subtypes in human peripheral blood mononuclear cells (PBMCs). Our results, confirmed by DNA sequencing, demonstrate the presence of m2, m3, m4, and m5 receptor subtypes in human PBMCs. The relative levels of muscarinic receptor subtypes fit the following pattern: m3 > m5 > m4 > m2. Our data provide strong evidence confirming previous pharmacological studies that suggested the existence of several subtypes of muscarinic receptors on human PBMCs. We cannot exclude the possibility that expression of receptor subtype depends on the lineage and/or activation status of the cell.

Cholinergic Agonists↗
PubMed1999

Radioligand binding assay of M1-M5 muscarinic cholinergic receptor subtypes in human peripheral blood lymphocytes.

Analysis of lymphocyte muscarinic cholinergic receptors using quantitative techniques such as radioligand binding assay is made difficult due to the low density of these sites and the lack of subtype-specific selectivity of most available muscarinic ligands. In this study, a combined kinetic and equilibrium labeling technique recently developed for brain tissue was used for labeling the five muscarinic cholinergic receptor subtypes in intact human peripheral blood lymphocytes. No specific muscarinic M1 receptor binding was detectable in human peripheral blood lymphocytes using [3H]-pirenzepine as a ligand. Labeling of M2-M5 muscarinic receptors using [3H]N-methyl-scopolamine (NMS) by occluding various receptor subtypes with muscarinic antagonist and mamba venom resulted in the labeling of M2-M5 receptors in brain as well as in human peripheral blood lymphocytes. The relative density of different receptor subtypes was M3 > M5 > M4 > M2. The development of a reproducible technique for assaying muscarinic cholinergic receptor subtypes expressed by human peripheral blood lymphocytes may contribute to clarify their role in lymphocyte function.

Adult↗
PubMed1995

5-HT2 receptor subtypes: a family re-united?

The current classification for 5-HT2 receptors accommodates three subtypes. In addition to the originally defined 5-HT2 receptor, sanctuary is now provided for the structurally related 5-HT1c receptor (now 5-HT2c) and at least one atypical 5-HT receptor subtype. The strong functional union of this family is reflected in the paucity of ligands that will discriminate between its subtypes and prompts some re-evaluation of the activities of compounds which may now be regarded as nonselective for the receptor subtypes in this class. In this article, Gordon Baxter and colleagues examine the pharmacology of both officially recognized and atypical 5-HT2 receptor subtypes. A number of novel selective agents are highlighted, some of which may prove useful for 5-HT2 receptor classification and, ultimately, clarify the mechanistic basis for current and future therapeutic strategies which target this receptor family.

Animals↗
PubMed1997

Gene targeting--homing in on alpha 2-adrenoceptor-subtype function.

The alpha-adrenoceptor was subdivided into three subtypes: alpha 2A-, alpha 2B- and alpha 2C-adrenoceptors almost ten years ago. Since then, the search has been on to discover and develop subtype-selective agonists and antagonists, but as yet no major breakthrough has been made. In the past year, several strains of genetically engineered mice have become available, either overexpressing, totally lacking or expressing heavily modified alpha 2-adrenoceptor subtypes. Ewen MacDonald, Brian Kobilka and Mika Scheinin describe how these mice may be utilized to elucidate the physiological functions of the receptor subtypes and the properties of future subtype-selective drugs.

Adrenergic alpha-Agonists↗
PubMed2003

Performance of a quantitative human immunodeficiency virus type 1 p24 antigen assay on various HIV-1 subtypes for the follow-up of human immunodeficiency type 1 seropositive individuals.

The heat-denatured signal-amplified p24 antigen assay is a low-cost test allowing the determination of plasma levels of HIV-1 p24 antigen in infected patients. This assay may be appropriate for monitoring disease progression in HIV seropositive patients in developing countries. Only a few data on the clinical validation of the test are available for HIV-1 non-subtypes B viruses that represent the vast majority of virus circulating in Africa. The present study was undertaken to evaluate and compare the performance of a heat-denatured signal-amplified p24 assay for the determination of p24 viral load in the plasma of individuals infected with different subtypes of HIV-1 and using the RT-PCR-based RNA viral load test as the gold standard. A total of 120 plasma samples from individuals infected with HIV-1 strains belonging to group M (subtypes A-->H) and group O, as well as recombinant strains, were tested in parallel with the heat-denatured signal-amplified p24 assay and the RNA viral load. Plasma p24 levels appeared to be correlated significantly with the plasma RNA viral loads (R=0.751, P<0.0001). The heat-denatured p24 antigen assay was capable of measuring the plasma level of p24 derived from all the HIV-1 subtypes and recombinants selected for this study, in contrast to the RNA viral load test which lacked sensitivity towards HIV-1 group O. The heat-denatured signal-amplified p24 assay is a reliable, sensitive and a more affordable tool that can be used for the follow-up of patients infected with B and non-B subtypes as well as recombinant forms of HIV-1 in developing countries.

Anti-HIV Agents↗