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PubMed1983

Distribution of transferrin (Tf) subtypes in Asian, Pacific and Australian Aboriginal populations: evidence for the existence of a new subtype TfC6.

Transferrin subtypes have been determined by isoelectric focussing of sera from 3,787 individuals in selected populations in the Asian, Pacific and Australian area. TfC1 and TfC2 were present in all populations studied. TfC3 was found to be polymorphic in a few populations only. The highest frequency of TfC2 was found in the Soliga (34%), an Indian tribal population, and the lowest TfC2 frequency was in Australian Aborigines (3%). In Pacific island populations TfC2 was found to be variable between 4 and 22%. A new subtype allele, TfC6, was observed at polymorphic frequency in Australian Aborigines.

Female↗

PubMed1990

GC subtyping and HIV infection in a Spanish population: no evidence of an association between GC subtypes and AIDS.

Group-specific component (GC) subtyping was performed by isoelectric focusing in 318 Spanish drug users at risk for infection or infected by HIV (85 HIV seronegatives, 111 HIV seropositives without symptoms, 89 seropositives with symptoms, 33 AIDS patients) and 187 healthy individuals. There was no significant association between GC subtypes and susceptibility to HIV infection and/or progression to AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed1991

Effects of angiotensin subtype 1 and subtype 2 receptor antagonists in normotensive versus hypertensive rats.

The purpose of this study was to examine in vivo the importance of angiotensin subtype 1 (AT1) versus subtype 2 (AT2) receptors in spontaneously hypertensive (hypertensive) versus normotensive Wistar-Kyoto (control) rats. Intravenous infusions of DuP 753, a selective AT1 receptor antagonist, abolished the pressor responses to intravenous infusions of angiotensin II in both strains, and the potency of DuP 753 in this regard was similar in the two strains. DuP 753 also abolished angiotensin II-induced aldosterone release in both strains; however, with respect to inhibiting angiotensin II-induced aldosterone release, DuP 753 was more potent in hypertensive compared with control rats. In hypertensive but not control rats, DuP 753 inhibited angiotensin II-induced aldosterone release at doses lower than required to inhibit angiotensin II-induced pressor responses. Intramesenteric infusions of DuP 753 abolished mesenteric vascular responses to intramesenteric infusions of angiotensin II with a similar potency in both strains. In control but not hypertensive rats, angiotensin II consistently potentiated noradrenergic neurotransmission in the mesenteric vascular bed, and this effect of angiotensin II was abolished by DuP 753. High doses of PD123177, a selective AT2 antagonist, did not influence any of the aforementioned effects of angiotensin II in either strain.(ABSTRACT TRUNCATED AT 250 WORDS)

Aldosterone↗

PubMed1993

Angiotensin subtype 1 blockade selectively potentiates adenosine subtype 2-mediated vasodilation.

A previous report demonstrated that infusion of adenosine into the forearm increased local vascular production of angiotensin II. We hypothesize that this increase in angiotensin II could attenuate the vasodilator response to adenosine subtype 2 (A2) receptor activation. The depressor and regional hemodynamic responses to the A2-selective adenosine agonist DPMA were measured in the presence and absence of angiotensin subtype 1 (AT1) receptor blockade (losartan, 10 mg/kg IV) in anesthetized rats. Losartan pretreatment (without versus with losartan) significantly potentiated DPMA-induced reductions in renal (-13 +/- 2% versus -22 +/- 4%, P < .05) and mesenteric (-11 +/- 2% versus -23 +/- 4%, P < .05) vascular resistances, resulting in a greater depressor response (-7 +/- 2 versus -18 +/- 3 mm Hg, P < .05). The decrease in hindquarter vascular resistance was not affected. To test the specificity of this interaction, we also evaluated nitroglycerin and nifedipine. Pretreatment with losartan had no effect on the responses to nitroglycerin, whereas the responses to nifedipine either were not affected or were attenuated (percent change in mesenteric vascular resistance: without losartan pretreatment, -30 +/- 1%; with losartan pretreatment, -24 +/- 2%, P < .05). To determine whether the decrease in arterial pressure after losartan pretreatment contributed to the potentiation of the DPMA-mediated effects, we infused nitroglycerin to lower mean arterial pressure comparably to losartan treatment. None of the hemodynamic responses to subsequent DPMA administration were affected. These data suggest that endogenous levels of angiotensin II, whether released locally or systemically, selectively attenuate the A2-mediated reductions in renal and mesenteric vascular resistances.

Adenosine↗

PubMed1992

Identification of endothelin receptor subtypes in human renal cortex and medulla using subtype-selective ligands.

High affinity and high density endothelin (ET)-binding sites were identified in membranes prepared from human kidney cortex and medulla. Saturation binding experiments performed in membranes prepared from cortex and medulla using [125I]ET-1 and [125I]ET-3 revealed that the proportion of [125I]ET-3-binding sites was 30-35% less than that of [125I]ET-1-binding sites. The apparent dissociation constants and maximum binding for [125I]ET-1 and [125I]ET-3 to membranes from cortex were 91 +/- 5 pM and 165 +/- 10 fmol/mg protein, and 117 +/- 9 pM and 110 +/- 7 fmol/mg protein, respectively, whereas in medulla they were 139 +/- 10 pM and 360 +/- 11 fmol/mg protein, and 142 +/- 11 pM and 245 +/- 15 fmol/mg protein, respectively. In the presence of 10 nM sarafotoxin-6c, which is selective for ETB receptors, [125I]ET-1 binding was decreased by 65-70%, whereas [125I]ET-3 binding was totally abolished, suggesting that 65-70% of [125I]ET-1 binding and 100% of [125I]ET-3 binding was to ETB receptors. This was further confirmed by the use of a cyclic pentapeptide [cyclo(D-Trp,D-Asp,L-Pro, D-Val,L-Leu)] (BQ123), which is selective for ETA receptors. In the presence of 1 microM BQ123, [125I]ET-1 binding was decreased by 25-30%, whereas [125I]ET-3 binding was unaffected, confirming that 30-35% of ET receptors belong to the ETA subtypes, and that [125I]ET-1 bound to both ETA and ETB receptors with the same high affinity, but [125I]ET-3 bound only to ETB receptors with high affinity. These results suggest that human kidney cortex and medulla contain ETA and ETB receptors in a ratio of 30:70, and that sarafotoxin-6c and BQ123 are valuable tools in identifying the subtype of ET receptors in various tissues.

Cell Membrane↗

PubMed2005

Dopamine receptor subtype 2 and somatostatin receptor subtype 5 expression influences somatostatin analogs effects on human somatotroph pituitary adenomas in vitro.

Dopamine (DA) and somatostatin (SRIF) receptor agonists inhibit growth hormone (GH) secretion by pituitary adenomas. We investigated DA subtype 2 receptor (DR2) and SRIF receptor (sst) subtypes 2 and 5 expression in 25 GH-secreting pituitary adenomas and tested in primary culture the effects on GH and prolactin (PRL) secretion of sst agonists selectively interacting with sst2 (BIM-23120), sst5 (BIM-23206), and sst2 and sst5 (BIM-23244). All adenomas expressed sst2; eight adenomas expressed both sst5 and DR2, eight sst5 but not DR2, and eight DR2 but not sst5. One tissue lacked expression of DR2 and sst5. GH secretion was inhibited by BIM-23120 in all samples, while it was reduced by BIM-23206 only in adenomas not expressing DR2. BIM-23120's inhibitory effects correlated with sst2 and DR2 expression, whereas DR2 expression correlated inversely with BIM-23206 inhibitory effects on GH secretion. In seven mixed GH-/PRL-secreting pituitary adenomas, PRL secretion was inhibited in sst5-expressing tumors by BIM-23206, but not by BIM-23120. BIM-23244 reduced PRL secretion only in adenomas expressing sst2, sst5 and DR2. sst5 and DR2 expression correlated directly with BIM23206 inhibitory effects on PRL secretion. Our results suggest that adenomas expressing DR2 are less likely to respond to clinically available SRIF analogs in terms of GH secretion inhibition. Therefore, drugs interacting also with DR2 might better control secretion of pituitary adenomas.

Acromegaly↗

PubMed2006

Three type 6 hepatitis C virus subgroups among blood donors in the Yangon area of Myanmar are identified as subtypes 6m and 6n, and a novel subtype by sequence analysis of the core region.

Previously, using phylogenetic analysis of NS5b sequences, we found that three type 6 variant subgroups (M6-1, M6-2 and M6-3) exist in Myanmar. According to the new nomenclature of hepatitis C, M6-1 and M6-2 belong to subtypes 6m and 6n, respectively, but M6-3 is unassigned. In this study, we sequenced and phylogenetically analyzed the core region of these type 6 variant subgroups. Serum samples assigned as 6m or 6n by NS5b sequence were also identified as 6 m or 6n by core region analysis. The M6-3 (sample name MYAN-3E-3) remained unassigned to a subgroup based on its core region analysis. The findings of this study suggest that either the core region or the NS5b region can be analyzed for HCV subtype classification.

Base Sequence↗

PubMed2005

Subtype-selective noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1).

This article describes recent advances in the development of subtype-selective, noncompetitive modulators of metabotropic glutamate receptor subtype 1 (mGluR1). mGluR1 plays an important role in modulating synaptic transmission and neuronal excitability via intracellular signal transduction pathways and has been implicated in a number of CNS disorders. Allosteric modulation of mGluR1 by potentiation and antagonism occurs through binding to the seven transmembrane domain. In addition to blocking agonist-dependent responses, many of the antagonists also show inverse-agonist activity by blocking constitutive receptor activity. Highly potent and selective mGluR1 radioligands have been used to evaluate receptor binding in vivo and in vitro. Some of these novel agents have demonstrated high levels of CNS exposure and receptor occupancy in vivo, as well as efficacy in a number of preclinical models of neurological disorders.

Allosteric Regulation↗

PubMed2001

Virulence and viremia characteristics of 1992 epizootic subtype IC Venezuelan equine encephalitis viruses and closely related enzootic subtype ID strains.

Following a 19-year hiatus, Venezuelan equine encephalitis (VEE) reemerged in western Venezuela in December 1992. This outbreak is important in understanding VEE emergence because phylogenetic studies imply that sympatric, enzootic, subtype ID VEE viruses mutated to generate the epizootic/epidemic. Although the 1992-1993 strains belong to subtype IC, a serotype implicated in extensive outbreaks during the 1960s and in 1995, relatively small numbers of human and equine cases occurred in 1992-1993. We, therefore, evaluated the pathogenicity of these Venezuelan enzootic ID and epizootic IC viruses to determine 1) if they exhibit phenotypes like those described previously for more distantly related enzootic and epizootic strains, and 2) if the 1992-1993 outbreak was limited by the inability of these IC viruses to exploit equines as amplification hosts. All strains were virulent in mice and guinea pigs, but were benign for cotton rats, natural hosts of enzootic viruses. However, only the IC strains produced equine disease, with mean peak viremias of 10(5) suckling mouse 50% lethal doses per mL serum, and some titers exceeding 10(7). These viremias approximate those observed previously with VEE strains isolated during more extensive epizootics, suggesting that efficient equine amplification did not limit the scope and duration of the 1992-1993 outbreak. Enzootic ID virus infection protected all horses from challenge with epizootic strain P676, supporting the hypothesis that epizootics bypass regions of enzootic transmission due to natural immunization of equines by enzootic VEE viruses.

Animals↗

PubMed2001

Functional calcitonin gene-related peptide subtype 2 receptors in porcine coronary arteries are identified as calcitonin gene-related peptide subtype 1 receptors by radioligand binding and reverse transcription-polymerase chain reaction.

Calcitonin gene-related peptide (CGRP) receptors are classified into CGRP subtype 1 (CGRP(1)) and CGRP subtype 2 (CGRP(2)) based on the affinity of the antagonist, human alpha (halpha)-CGRP(8-37). halpha-CGRP(8-37) antagonizes CGRP(1) receptor-mediated responses with high affinity (K(B) < 100 nM) and antagonizes CGRP(2) receptor-mediated responses with low affinity (K(B) > 1 microM). CGRP(2) receptors have been previously reported to mediate relaxation of large porcine coronary arteries because this action is antagonized with low affinity by halpha-CGRP(8-37). In the present study, we used reverse transcription-polymerase chain reaction, radioligand binding, and values from our previously reported isolated tissue experiments to compare the CGRP receptor in porcine coronary arteries with the porcine CGRP(1) receptor stably expressed in human embryonic kidney (HEK) 293 cells. We identified calcitonin receptor-like receptor and receptor activity modifying protein 1 mRNA in coronary arteries. We also found that the ligand binding characteristics of the CGRP receptor in coronary arteries and the cloned CGRP(1) receptor were highly similar. K(I) values for halpha-CGRP(8-37) were 6.6 and 5.7 nM in porcine coronary arteries and the cloned CGRP(1) receptor, respectively. The affinities (K(B)) of halpha-CGRP(8-37) and five other antagonists were 22- to 707-fold lower in functional experiments measuring relaxation of coronary arteries than in radioligand binding experiments. Despite this difference in absolute affinity values, there was a high correlation of the rank order of affinity for the antagonists determined by the two methods. Thus halpha-CGRP(8-37) antagonizes CGRP-induced relaxation of porcine coronary arteries with low affinity at the CGRP(1) receptor. Taken together, these data do not support the existence of the CGRP(2) receptor.

Animals↗

PubMed1992

Identification of endothelin receptor subtypes in rat kidney cortex using subtype-selective ligands.

125I-Endothelin (ET)-1 and 125I-ET-3 displayed specific, saturable, and high affinity binding to membranes prepared from rat kidney cortex. Saturation binding experiments using 125I-ET-1 and 125I-ET-3 revealed that 125I-ET-3 binding sites were 40-50% less abundant than 125I-ET-1 binding sites. The dissociation constants (Kd) and maximum binding (Bmax) for 125I-ET-1 and 125I-ET-3 with these membranes were 218 +/- 23 pM and 275 +/- 20 fmol/mg of protein and 207 +/- 19 pM and 113 +/- 17 fmol/mg of protein, respectively. In the presence of 10 nM sarafotoxin 6c, a selective agonist for ETb receptors, 125I-ET-1 binding was decreased by 45-50% and 125I-ET-3 binding was totally abolished, suggesting that approximately 40-50% of kidney cortex ET receptors are of the ETB subtype and that 125I-ET-1 binds to both ETA and ETB receptors with the same high affinity, whereas 125I-ET-3 binds to only ETB receptors with high affinity. In addition, in the presence of BQ123 [cyclo(D-Trp,D-Asp,L-Pro,D-Val,L-Leu)], a selective antagonist for ETA receptors, 125I-ET-1 binding was decreased by 50%, whereas 125I-ET-3 binding was unaffected. Our results strongly suggest that rat kidney cortex contains ETA and ETB receptors in a 50:50 ratio and that sarafotoxin 6c and BQ123 are valuable tools in identifying the subtypes of ET receptors in various tissues.

Amino Acid Sequence↗

PubMed1992

Further characterization of neuropeptide Y receptor subtypes using centrally truncated analogs of neuropeptide Y: evidence for subtype-differentiating effects on affinity and intrinsic efficacy.

Previous attempts to classify neuropeptide Y receptor subtypes suffered from relying only on carboxyl-terminal analogs and fragments of neuropeptide Y. We have tested the potency and affinity of chemically different compounds, i.e., centrally truncated analogs of neuropeptide Y, in three Y1-like (Ca2+ mobilization in HEL cells, blood pressure increases in pithed rats, and 125I-neuropeptide Y binding in SK-N-MC cells) and two Y2-like (125I-neuropeptide Y binding to rabbit kidney membranes and presynaptic inhibition in rat vas deferens) model systems of neuropeptide Y receptors. Our data confirm the concept of two major subclasses of neuropeptide Y receptors, with some centrally truncated neuropeptide Y analogs having high affinity for Y2-like and low affinity for Y1-like neuropeptide Y receptors. Some of the truncated neuropeptide Y analogs are antagonists at Y1-like receptors and (possibly partial) agonists at Y2-like receptors. Our data also indicate that amino acid residues distal from the amino- and carboxyl-terminal ends of the peptide may subtype-selectively affect affinity and intrinsic efficacy of peptide agonists at neuropeptide Y receptors.

Amino Acid Sequence↗

PubMed1989

Alpha-2A and alpha-2B adrenergic receptor subtypes: attenuation of cyclic AMP production in cell lines containing only one receptor subtype.

At least two subtypes of alpha-2 adrenergic receptors have been identified on the basis of antagonist affinities as determined mainly by radioligand binding assays. The human platelet and the HT29 human colonic adenocarcinoma cell contain alpha-2A adrenergic receptors, whereas the neonatal rat lung and the NG108 neuroblastoma X glioma hybrid cell contain the alpha-2B adrenergic receptor. Using the attenuation of the cyclic AMP accumulation as a functional assay, the affinities of various antagonists for the alpha-2 adrenergic receptor were determined in HT29 and NG108 cell lines. Dose-response curves to 5-bromo-6-(2-imidazoline-2-yl-amino)quinoxaline (UK 14,304) an alpha-2 adrenergic agonist, were generated in the absence and presence of three concentrations of various antagonists. Schild regressions were used to determine pA2 values and then dissociation constants (KB value) were calculated. Whereas phentolamine and yohimbine were equipotent at the receptor in the two cell lines, 2-(2,4-(O-methoxyphenyl)-piper-azin-1-yl)ethyl-4,4-dimethyl-1,3-(2 H,4H)- isoquinolindione (ARC-239) and prazosin were 100- and 30-fold more potent in the NG108 cell line than in the HT29 cell. These potency ratios determined from functional experiments are the same as those obtained from radioligand binding experiments. These functional data are consistent with the previous and more extensive binding data, and thus support the existence and definition of alpha-2A and alpha-2B adrenergic receptor subtypes.

Animals↗

PubMed1985

Molecular cloning and DNA sequence analysis of genes encoding cytotoxic T lymphocyte-defined HLA-A3 subtypes: the E1 subtype.

Influenza-specific cytotoxic T cells restricted by HLA-A3 and allogeneic CTL specific for HLA-A3 recognize differences between serologically indistinguishable HLA-A3 antigens. Previous biochemical studies have indicated that such differential recognition can be explained by alterations in the primary structure of class I heavy chains. Characterization of these sequence differences may therefore identify portions of the class I molecule that form determinants recognized by CTL. In this study, we describe the cloning and sequencing of an HLA-A3 subtype from donor E1 (E1-A3). Cloning of the gene encoding E1-A3 was simplified by determining that a 15.5-kb BamHI fragment contains the complete gene and is characteristic of HLA-A3 and only one other class I gene (HLA-A11). Comparison of the E1-A3 sequence to that of a previously sequenced HLA-A3 gene for exons encoding extracellular class I domains revealed three nucleotide differences. All of these differences were located within a discrete region of exon 3 (encoding the alpha 2 domain) and result in a change of two amino acids, at positions 152 (Glu----Val) and 156 (Leu----Gln). This finding suggests that these amino acids are crucial for the information of a determinant recognized by CTL. Furthermore, the altered nucleotide sequence of E1-A3 is identical to the sequence of the HLA-Aw24 gene for codons 128 to 161. These observations of multiple clustered changes in the E1-A3 subtype (relative to the prototype sequence) and identity of the altered sequence with the sequence of another class I gene support the concept that gene conversion is a primary mechanism for the generation of class I polymorphism.

Adult↗

PubMed1984

Differences in evolutionary stability among mammalian H1 subtypes. Implications for the roles of H1 subtypes in chromatin.

The metabolic and developmental properties that differentiate five H1 subtypes of the mouse, H1a-H1e, are shown to have been conserved in the course of mammalian evolution. The structures of the subtypes, however, as judged by their mobilities in two-dimensional gel electrophoresis, have been conserved to varying extents. H1a and H1c have undergone the most structural variation, each having a different electrophoretic mobility in every species examined. H1b is much less varied, while H1d and H1e are invariant by these electrophoretic criteria. These results suggest that H1a and -c differ fundamentally from H1b, -d, and -e in their interactions with other chromatin components. It is suggested that this difference is in the ability to promote the coiling of 10-nm chromatin fibers into higher order chromatin structures.

Animals↗

PubMed1993

Genetic heterogeneity in neuronal ceroid lipofuscinosis (NCL): evidence that the late-infantile subtype (Jansky-Bielschowsky disease; CLN2) is not an allelic form of the juvenile or infantile subtypes.

The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by the accumulation of autofluorescent lipopigment in neurons and other cell types. Inheritance is autosomal recessive. Three main childhood subtypes are recognized: infantile (Haltia-Santavuori disease; MIM 256743), late infantile (Jansky-Bielschowsky disease; MIM 204500), and juvenile (Spielmeyer-Sjögren-Vogt, or Batten, disease; MIM 204200). The gene loci for the juvenile (CLN3) and infantile (CLN1) types have been mapped to human chromosomes 16p and 1p, respectively, by linkage analysis. Linkage analysis of 25 families segregating for late-infantile NCL has excluded these regions as the site of this disease locus (CLN2). The three childhood subtypes of NCL therefore arise from mutations at distinct loci.

Alleles↗

PubMed1998

Determination of somatostatin receptor subtype 2 in carcinoid tumors by immunohistochemical investigation with somatostatin receptor subtype 2 antibodies.

We have shown previously that expression of mRNA for somatostatin receptor subtype 2 (sst2) detected by in situ hybridization correlates to therapeutic outcome in patients with carcinoid tumors treated with somatostatin analogues. However, in situ hybridization is laborious and not practical in clinical routine work. We have, therefore, developed polyclonal antibodies directed against sst2 that may be used for immunohistochemistry on tissue specimens. The staining is specific and is highly correlated to expression of mRNA for sst2 (P < 0.01) as well as to tracer uptake at somatostatin receptor scintigraphy (P < 0.01). There is also a good correlation to the therapeutic response in carcinoid patients treated with somatostatin analogues (P < 0.05). Of 35 patients with carcinoid tumors included in this investigation, 25 stained positive with the antibodies. Twenty-two of these were investigated by somatostatin receptor scintigraphy and showed tracer uptake in metastases. An additional two patients that did not stain with the antibodies showed pathological uptake of the tracer in metastases, which might indicate binding to somatostatin receptor subtype 5. None of the 10 patients without positive immunostaining responded to somatostatin analogue treatment, whereas patients with a positive stain had a biochemical response or remained stable during treatment. Thus, these antibodies may be used to determine the presence of sst2 in carcinoid tumors and to select patients suitable for somatostatin analogue treatment. The method is easily applicable in clinical practice.

Animals↗

PubMed1986

Investigation of a case of subtype IIC von Willebrand disease: characterization of the variability of this subtype.

A variant of von Willebrand disease (vWD) has been identified in a 19-year-old woman with a severe bleeding syndrome. She had a very prolonged bleeding time (over 20 min), 24 U/dl factor VIII coagulant activity (F.VIII:C), 16 U/dl von Willebrand factor antigen (vWF:Ag), no ristocetin cofactor activity, and an anodal mobility of vWF:Ag on crossed immunoelectrophoresis (CIE). vWF:Ag was markedly reduced in her platelet lysate. In plasma and platelets, SDS-agarose electrophoresis consistently demonstrated the absence of large multimers, a relatively increased concentration of the fastest-moving multimer, and gross abnormalities of the internal structure of each vWF multimeric unit. Five members from the maternal side of the family had a double vWF:Ag peak by CIE and a relative increase of the fastest-moving vWF multimer by SDS-agarose electrophoresis; no quantitative or qualitative vWF defects were found in the paternal side of the family. The pattern of the findings in the propositus and her family is similar to those of type IIC vWD. However, there are some unique characteristics suggesting phenotypic variability in this subtype, such as low level of platelet vWF:Ag and the absence of increase of vWF after DDAVP administration.

Adult↗