scholarly journals Stereoselectivity of Ins(1,3,4,5)P4 recognition sites: implications for the mechanism of the Ins(1,3,4,5)P4-induced Ca2+ mobilization

1993 ◽  
Vol 294 (1) ◽  
pp. 191-194 ◽  
Author(s):  
R A Wilcox ◽  
R A Challiss ◽  
G Baudin ◽  
A Vasella ◽  
B V Potter ◽  
...  
Keyword(s):  
Binding Site ◽  
Specific Binding ◽  
Specific Interaction ◽  
Neuroblastoma Cells ◽  
Dependent Manner ◽  
Binding Studies ◽  
Concentration Dependent Manner ◽  
Human Neuroblastoma ◽  
Specific Binding Sites ◽  
Ic50 Values

Ins(1,3,4,5)P4 was able to mobilize the entire Ins(1,4,5)P3-sensitive intracellular Ca2+ store in saponin-permeabilized SH-SY5Y human neuroblastoma cells in a concentration-dependent manner, yielding an EC50 value of 2.05 +/- 0.45 microM, compared with 0.14 +/- 0.03 microM for Ins(1,4,5)P3. However, L-Ins(1,3,4,5)P4 [= D-Ins(1,3,5,6)P4] failed to cause mobilization of intracellular Ca2+ at concentrations up to 100 microM. Binding studies using pig cerebellar membranes as a source of both Ins(1,4,5)P3/Ins(1,3,4,5)P4-specific binding sites have revealed a marked contrast in their stereospecificity requirements. Ins(1,4,5)P3-receptors from pig cerebella exhibited stringent stereospecificity, L-Ins(1,4,5)P3 and L-Ins(1,3,4,5)P4 were > 1000-fold weaker, whereas Ins(1,3,4,5)P4 (IC50 762 +/- 15 nM) was only about 40-fold weaker than D-Ins(1,4,5)P3 (IC50 20.7 +/- 9.7 nM) at displacing specific [3H]Ins(1,4,5)P3 binding from an apparently homogeneous Ins(1,4,5)P3 receptor population. In contrast, the Ins(1,3,4,5)P4-binding site exhibited poor stereoselectivity. Ins(1,3,4,5)P4 produced a biphasic displacement of specific [32P]Ins(1,3,4,5)P4 binding, with two-site analysis revealing KD values for high- and low-affinity sites of 2.1 +/- 0.5 nM and 918 +/- 161 nM respectively. L-Ins(1,3,4,5)P4 also produced a biphasic displacement of specific [32P]Ins(1,3,4,5)P4 binding which was less than 10-fold weaker than with D-Ins(1,3,4,5)P4 (IC50 values for the high- and low-affinity sites of 17.2 +/- 3.7 nM and 3010 +/- 542 nM respectively). Therefore, although L-Ins(1,3,4,5)P4 appears to be a high-affinity Ins(1,3,4,5)P4-binding-site ligand in pig cerebellum, it is a very weak agonist at the Ca(2+)-mobilizing receptors of permeabilized SH-SY5Y cells. We suggest that the ability of D-Ins(1,3,4,5)P4 to access intracellular Ca2+ stores may derive from specific interaction with the Ins(1,4,5)P3- and not the Ins(1,3,4,5)P4-receptor population.

Phosphatidylserine and Oxidized Phosphatidylethanolamine Interact with Protein C Inhibitor (PCI) and Modify Its Activity.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1026-1026
Author(s):  
Julia M. Malleier ◽  
Olga Oskolkova ◽  
Valery Bochkov ◽  
Ingrid Jerabek ◽  
Barbora Sokolikova ◽  
...  
Keyword(s):  
Complex Formation ◽  
Binding Site ◽  
Protein C ◽  
Specific Binding ◽  
Dependent Manner ◽  
Heparin Binding ◽  
Binding Studies ◽  
Heparin Binding Site ◽  
Protein C Inhibitor

Abstract Protein C Inhibitor (PCI) is a non-specific serine protease inhibitor (serpin), which inhibits many proteases of the coagulation and fibrinolytic systems. PCI binds to heparin, and heparin enhances the interaction of PCI with most proteases. It has been shown by Nishioka et al. (1998) that PCI also binds to phosphatidylethanolamine (PE), a major phospholipid of the inner leaflet of cell membranes, and that PCI inhibits phospholipid-bound activated protein C (APC) efficiently. These data suggest a biological role of PE exposed on the surface of activated platelets and microvesicles for the regulation of PCI activity in vivo. To further analyze to which extent phospholipids could play a role for the regulation of PCI activity, we studied the interaction of PCI with different phospholipids and their oxidized forms. We investigated binding of PCI to phospholipids [PE, phosphatidylserine (PS), and phosphatidylcholine (PC) and their oxidized forms] immobilized on microtiter plates. To control for specificity of the binding, studies were performed in the absence and presence of varying concentrations of different phospholipids and heparin in the fluid phase. These studies revealed specific binding of PCI to oxidized and to unoxidized PS, and to oxidized but not to unoxidized PE. No binding was seen with oxidized or unoxidized PC. Binding to ox-PE and PS was confirmed by a mobility shift of PCI in native PAGE. Binding of PCI to oxidized PE and PS was competed by heparin. Furthermore, PCI, in which the heparin-binding site (Lys276-Lys277-Arg278) in the H-helix was mutated to Ala-Ala-Gly, no longer bound to ox-PE or PS. We also investigated the effect of phospholipids on the interaction of PCI with its target proteases APC and urokinase (uPA) by analyzing inhibition of amidolytic activity and complex formation on SDS-PAGE. PS (oxidized as well as unoxidized) and oxidized PE stimulated the inhibition of APC and uPA by PCI and enhanced complex formation of PCI with these proteases. No stimulatory effect of phospholipids was seen with the PCI mutant lacking the heparin-binding site. The effect of oxidized PE and PS on the interaction of PCI with APC was strongly dependent on the presence of Ca++. In the absence of Ca++ oxidized PE and PS interfered in a dose-dependent manner with the interaction of APC with PCI; and this effect was antagonized by heparin. Therefore, binding of both, APC (Ca++-dependent) as well as PCI (Ca++-independent), to PS or oxidized PE are required for the stimulating effect of these phospholipids on APC-inhibition by PCI. The stimulatory effect of PS and oxidized PE seems to be specific for PCI since it was not seen with antithrombin III, another heparin-binding serpin. In conclusion, our data indicate that in addition to heparin and glycosaminoglycans also certain phospholipids (oxidized PE and PS) can stimulate the activity of the non-specific serpin PCI. Binding to these phospholipids seems to involve the heparin-binding site of PCI. Exposure of oxidized PE and /or PS may therefore be important for the regulation of PCI-activity in vivo. This may play a role at sites of inflammation and/or apoptosis (e.g. on atherosclerotic plaques) or other sites where ox-PE or PS are exposed (e.g. in myotube fusion). In fact, in mouse embryos PCI antigen seems to co-localize with PS at sites of cell fusion and apoptosis.

Cyanidin Protects SH-SY5Y Human Neuroblastoma Cells from 1-Methyl-4-Phenylpyridinium-Induced Neurotoxicity

Pharmacology ◽  
2018 ◽  
Vol 102 (3-4) ◽  
pp. 126-132 ◽  
Author(s):  
Jian Chen ◽  
Jian Sun ◽  
Julian Jiang ◽  
Jie Zhou
Keyword(s):  
Fruits And Vegetables ◽  
Neuroblastoma Cells ◽  
Dependent Manner ◽  
Neuroprotective Effects ◽  
Concentration Dependent Manner ◽  
Human Neuroblastoma ◽  
Mitochondrial Oxidative Stress ◽  
Induced Apoptosis ◽  
First Time ◽  
Shed Light

Cyanidin is an anthocyanidin extracted from a variety of fruits and vegetables. Cyanidin showed benefits against diabetes, cancer, and atherosclerosis. However, the potential neuroprotective effects of cyanidin against Parkinson’s disease (PD) have not been examined. Indicated concentrations of cyanidin (1, 3, 10, and 30 μmol/L) were incubated together with 0.5 mmol/L 1-methyl-4-phenylpyridinium (MPP+) to human neuroblastoma SH-SY5Y cells. We found cyanidin prevented MPP+-induced cell demise in a concentration-dependent manner. Cyanidin significantly reduced MPP+-induced apoptosis, this is reflected by decreased TdT-mediated dUTP nick-end labeling staining and caspase-3 expressions. Further, MPP+ increased the Bax/Bcl-2 ratio, which was partly reversed by cyanidin. We also found cyanidin attenuated the MPP+-induced mitochondrial oxidative stress as revealed by decreased MitoSOX staining. Taken together, these data for the first time indicated the ­neuroprotective effects of cyanidin against MPP+-induced ­SH-SY5Y cell death. These findings shed light on the potential implications of cyanidin for PD treatment.

Chickpea (Cicer arietinum L.) Lectin Exhibit Inhibition of ACE-I, α-amylase and α-glucosidase Activity

2019 ◽  
Vol 26 (7) ◽  
pp. 494-501 ◽  
Author(s):  
Sameer Suresh Bhagyawant ◽  
Dakshita Tanaji Narvekar ◽  
Neha Gupta ◽  
Amita Bhadkaria ◽  
Ajay Kumar Gautam ◽  
...  
Keyword(s):  
Biological Effects ◽  
Exchange Chromatography ◽  
Health Concern ◽  
Carbohydrate Binding ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Chickpea Lectin

Background: Diabetes and hypertension are the major health concern and alleged to be of epidemic proportions. This has made it a numero uno subject at various levels of investigation. Glucosidase inhibitor provides the reasonable option in treatment of Diabetes Mellitus (DM) as it specifically targets post prandial hyperglycemia. The Angiotensin Converting Enzyme (ACE) plays an important role in hypertension. Therefore, inhibition of ACE in treatment of elevated blood pressure attracts special interest of the scientific community. Chickpea is a food legume and seeds contain carbohydrate binding protein- a lectin. Some of the biological properties of this lectin hitherto been elucidated. Methods: Purified by ion exchange chromatography, chickpea lectin was tested for its in vitro antioxidant, ACE-I inhibitory and anti-diabetic characteristic. Results: Lectin shows a characteristic improvement over the synthetic drugs like acarbose (oral anti-diabetic drug) and captopril (standard antihypertensive drug) when, their IC50 values are compared. Lectin significantly inhibited α-glucosidase and α-amylase in a concentration dependent manner with IC50 values of 85.41 ± 1.21 ҝg/ml and 65.05 ± 1.2 µg/ml compared to acarbose having IC50 70.20 ± 0.47 value of µg/ml and 50.52 ± 1.01 µg/ml respectively. β-Carotene bleaching assay showed antioxidant activity of lectin (72.3%) to be as active as Butylated Hydroxylanisole (BHA). In addition, lectin demonstrated inhibition against ACE-I with IC50 value of 57.43 ± 1.20 µg/ml compared to captopril. Conclusion: Lectin demonstrated its antioxidant character, ACE-I inhibition and significantly inhibitory for α-glucosidase and α-amylase seems to qualify as an anti-hyperglycemic therapeutic molecule. The biological effects of chickpea lectin display potential for reducing the parameters of medically debilitating conditions. These characteristics however needs to be established under in vivo systems too viz. animals through to humans.

Cytotoxic Effects of Ferula Latisecta on Human Glioma U87 Cells

Drug Research ◽  
2019 ◽  
Vol 69 (12) ◽  
pp. 665-670 ◽  
Author(s):  
Mohammad Jalili-Nik ◽  
Hamed Sabri ◽  
Ehsan Zamiri ◽  
Mohammad Soukhtanloo ◽  
Mostafa Karimi Roshan ◽  
...  
Keyword(s):  
Enzymatic Activity ◽  
Gelatin Zymography ◽  
Annexin V ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Ic50 Values ◽  
Induced Apoptosis ◽  
Natural Herb ◽  
First Time ◽  
U87 Cells

AbstractGlioblastoma multiforme (GBM) is the fatal type of astrocytic tumors with a survival rate of 12 months. The present study, for the first time, evaluated the cytotoxic impacts of Ferula latisecta (F. latisecta) hydroalcoholic extract on U87 GBM cell line. The MTT assay measured the cellular toxicity following 24- and 48 h treatment with various doses of F. latisecta (0–800 μg/mL). Apoptosis was evaluated by an Annexin V/propidium iodide (PI) staining 24 h after treatment by F. latisecta. Moreover, to determine the cellular metastasis of U87 cells, we used a gelatin zymography assay (matrix metalloproteinase [MMP]-2/-9 enzymatic activity). The outcomes showed that F. latisecta mitigated the viability of U87 cells in a concentration- and time-dependent manner with IC50 values of 145.3 and 192.3 μg/mL obtained for 24- and 48 h treatments, respectively. F. latisecta induced apoptosis in a concentration-dependent manner after 24 h. Also, MMP-9 activity was significantly decreased following 24 h after treatment concentration-dependently with no change in MMP-2 enzymatic activity. This study showed that F. latisecta induced cytotoxicity and apoptosis, and mitigated metastasis of U87 GBM cells. Hence, F. latisecta could be beneficial as a promising natural herb against GBM after further studies.

Direct interaction of the tau 1 transactivation domain of the human glucocorticoid receptor with the basal transcriptional machinery

1993 ◽  
Vol 13 (1) ◽  
pp. 399-407
Author(s):  
I J McEwan ◽  
A P Wright ◽  
K Dahlman-Wright ◽  
J Carlstedt-Duke ◽  
J A Gustafsson
Keyword(s):  
Glucocorticoid Receptor ◽  
Protein Interactions ◽  
Core Promoter ◽  
Specific Interaction ◽  
Direct Interaction ◽  
Dependent Manner ◽  
Transactivation Domain ◽  
Yeast Saccharomyces Cerevisiae ◽  
Concentration Dependent Manner

We have used a yeast (Saccharomyces cerevisiae) cell free transcription system to study protein-protein interactions involving the tau 1 transactivation domain of the human glucocorticoid receptor that are important for transcriptional transactivation by the receptor. Purified tau 1 specifically inhibited transcription from a basal promoter derived from the CYC1 gene and from the adenovirus 2 major late core promoter in a concentration-dependent manner. This inhibition or squelching was correlated with the transactivation activity of tau 1. Recombinant yeast TATA-binding protein (yTFIID), although active in vitro, did not specifically reverse the inhibitory effect of tau 1. In addition, no specific interaction between tau 1 and yTFIID could be shown in vitro by affinity chromatography. Taken together, these results indicate that the tau 1 transactivation domain of the human glucocorticoid receptor interacts directly with the general transcriptional apparatus through some target protein(s) that is distinct from the TATA-binding factor. Furthermore, this assay can be used to identify interacting factors, since after phosphocellulose chromatography of a whole-cell yeast extract, a fraction that contained an activity which selectively counteracted the squelching effect of tau 1 was found.

Glycine Binding Site of the Synaptic NMDA Receptor in Subpostremal NTS Neurons

2005 ◽  
Vol 94 (1) ◽  
pp. 147-152 ◽  
Author(s):  
Vander Baptista ◽  
Wamberto Antonio Varanda
Keyword(s):  
Nmda Receptor ◽  
Binding Site ◽  
Reversal Potential ◽  
Postsynaptic Membrane ◽  
Bathing Solution ◽  
Total Charge ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Autonomic Reflex ◽  
Transverse Slice

The nucleus of the tractus solitarius (NTS) plays an important role in the control of several autonomic reflex functions and has glutamate and GABA as main neurotransmitters. In this work, we used patch-clamp recordings in transverse slice preparations from rats to study whether the glycine binding site of the N-methyl-d-aspartate (NMDA) receptor is saturated or not in neurons of the subpostremal NTS. Except at hyperpolarized voltages and close to the reversal potential, glycine potentiated the NMDA responses in a concentration-dependent manner. The total charge transferred by glutamatergic currents was enhanced by glycine (500 μM; from 28 ± 13 to 42 ± 18 pC at +50 mV, n = 7, P < 0.05). Glycine increased the conductance of the postsynaptic membrane, without altering its reversal potential, both in the presence (from 2.4 ± 0.06 to 3.4 ± 0.09 nS; n = 7) and absence (from 3.1 ± 0.06 to 4.4 ± 0.10 nS; n = 8) of Mg2+ in the bathing solution. d-serine, in the presence of strychnine, also increased the amplitude of the NMDA component (by 68 ± 19%, P < 0.05, n = 5). The membrane potential was hyperpolarized (16 ± 6 mV, n = 8) by glycine, suggesting the presence of inhibitory glycinergic receptors. Our results indicate that the glycine site of the NMDA receptor in neurons of the subpostremal NTS is not saturated and that glycine may act as a modulator of the NMDA transmission in this nucleus.

PKCϵ has an alcohol-binding site in its second cysteine-rich regulatory domain

2009 ◽  
Vol 421 (3) ◽  
pp. 405-413 ◽  
Author(s):  
Joydip Das ◽  
Satyabrata Pany ◽  
Ghazi M. Rahman ◽  
Simon J. Slater
Keyword(s):  
Protein Kinase ◽  
Binding Site ◽  
Maximum Effect ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Kinase C ◽  
C1 Domain ◽  
Pkc Protein Kinase C ◽  
And Function

Alcohols regulate the expression and function of PKC (protein kinase C), and it has been proposed that an alcohol-binding site is present in PKCα in its C1 domain, which consists of two cysteine-rich subdomains, C1A and C1B. A PKCϵ-knockout mouse showed a significant decrease in alcohol consumption compared with the wild-type. The aim of the present study was to investigate whether an alcohol-binding site could be present in PKCϵ. Here we show that ethanol inhibited PKCϵ activity in a concentration-dependent manner with an EC50 (equilibrium ligand concentration at half-maximum effect) of 43 mM. Ethanol, butanol and octanol increased the binding affinity of a fluorescent phorbol ester SAPD (sapintoxin-D) to PKCϵC1B in a concentration-dependent manner with EC50 values of 78 mM, 8 mM and 340 μM respectively, suggesting the presence of an allosteric alcohol-binding site in this subdomain. To identify this site, PKCϵC1B was photolabelled with 3-azibutanol and 3-azioctanol and analysed by MS. Whereas azibutanol preferentially labelled His236, Tyr238 was the preferred site for azioctanol. Inspection of the model structure of PKCϵC1B reveals that these residues are 3.46 Å (1 Å=0.1 nm) apart from each other and form a groove where His236 is surface-exposed and Tyr238 is buried inside. When these residues were replaced by alanine, it significantly decreased alcohol binding in terms of both photolabelling and alcohol-induced SAPD binding in the mutant H236A/Y238A. Whereas Tyr238 was labelled in mutant H236A, His236 was labelled in mutant Y238A. The present results provide direct evidence for the presence of an allosteric alcohol-binding site on protein kinase Cϵ and underscore the role of His236 and Tyr238 residues in alcohol binding.

scholarly journals The tumour suppressor p53 regulates the expression of amyloid precursor protein (APP)

2009 ◽  
Vol 418 (3) ◽  
pp. 643-650 ◽  
Author(s):  
Ascensión Cuesta ◽  
Alberto Zambrano ◽  
María Royo ◽  
Angel Pascual
Keyword(s):  
Transcription Factor ◽  
Amyloid Precursor Protein ◽  
Dna Sequences ◽  
Primary Cultures ◽  
Neuroblastoma Cells ◽  
Dominant Negative ◽  
Precursor Protein ◽  
Human Neuroblastoma Cell ◽  
Dependent Manner ◽  
Human Neuroblastoma

The expression of the APP (amyloid precursor protein), which plays a key role in the development of AD (Alzheimer's disease), is regulated by a variety of cellular mediators in a cell-dependent manner. In this study, we present evidence that p53 regulates the expression of the APP gene in neuroblastoma cells. Transient expression of ectopic p53, activation of endogenous p53 by the DNA-damaging drug camptothecin or Mdm2 (murine double minute 2) depletion decreases the intracellular levels of APP in murine N2aβ neuroblastoma cells. This effect was also observed in primary cultures of rat neurons as well as in SH-SY5Y cells, a human neuroblastoma cell line. Transient transfection studies using plasmids that contain progressive deletions of the 5′ region of the gene demonstrate that p53 represses APP promoter activity through a mechanism that is mediated by DNA sequences located downstream of the transcription start site (+55/+101). Accordingly, expression of a dominant-negative p53 mutant significantly increases the transcriptional activity of the APP promoter. In addition, results obtained in gel mobility-shift assays show that p53 does not bind to the +55/+101 APP region, although it reduces binding of the transcription factor Sp1 (stimulating protein 1). Reduction of Sp1 binding after activation of p53 with camptothecin was also observed in chromatin immunoprecipitation assays. Altogether, our results strongly suggest a mechanism by which p53 precludes binding of Sp1 to DNA, and therefore the stimulation of the APP promoter by this transcription factor.

Mapping the Protease Activated Receptor 4 (PAR4) Homodimer Interface.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 773-773
Author(s):  
Marvin T Nieman
Keyword(s):  
Conflicts Of Interest ◽  
Specific Interaction ◽  
Resonance Energy Transfer ◽  
Resonance Energy ◽  
Receptor Activation ◽  
Dependent Manner ◽  
Intracellular Loop ◽  
Concentration Dependent Manner ◽  
Platelet Surface

Abstract Abstract 773 Thrombin activates platelets by binding and cleaving protease activated receptors 1 and 4 (PAR1 and PAR4). PAR1 and PAR4 communicate with each other to lower the concentration of thrombin required for PAR4 activation (Nieman Biochemistry, 2008). In addition, PAR1 and PAR4 form homo and heterodimers. However, where these receptors interact has not been defined and it is not known if dimerization influences receptor activation, downstream signaling, or both. Since PAR4 activation is important on human and mouse platelets, we sought to characterize the interaction site between PAR4 homodimers. Using bioluminescence resonance energy transfer (BRET), we mapped the PAR4 homodimer interface. The PAR4 homodimers show a specific interaction as indicated by a hyperbolic BRET signal in response to increasing PAR4-GFP expression with a fixed concentration of PAR4-Rluc. The threshold maximum BRET signal was disrupted in a concentration-dependent manner by unlabeled PAR4. In contrast, the unrelated G-protein coupled receptor, rhodopsin, was unable to disrupt the BRET signal indicating that the disruption of the PAR4 homodimer is a specific interaction. We have mapped the region required for PAR4 homodimer formation using chimeras between rhodopsin and PAR4. PAR4 does not interact with rhodopsin in BRET assays. Using a library of rho-PAR4 chimeras that have the junction at the beginning of transmembrane (TM) 2, 3, 4, 5, 6 or 7, we determined where dimer formation is restored. When the junction is placed at the beginning of TM4 or TM5, the chimera does not interact with PAR4-WT. In contrast, when the junction is moved to the end of TM2, the BRET signal is restored. These results indicate that the region on PAR4 required for homodimer formation encompasses a 63 amino acid region that includes the first extracellular loop, TM3 and the second intracellular loop. These studies establish techniques that may be used to define the interactions between other GPCRs found on the platelet surface. These receptor-receptor interactions may be another level of regulation of agonist activity and platelet function in vivo and may provide novel targets for anti-platelet therapies. Disclosures: No relevant conflicts of interest to declare.

Autoradiographic detection of kinin receptors in the human medulla of control, hypertensive, and diabetic donors

2002 ◽  
Vol 80 (4) ◽  
pp. 249-257 ◽  
Author(s):  
Hudson de Sousa Buck ◽  
Brice Ongali ◽  
Gaétan Thibault ◽  
Charles J Lindsey ◽  
Réjean Couture
Keyword(s):  
Receptor Binding ◽  
Binding Sites ◽  
Specific Binding ◽  
Inferior Olivary Nucleus ◽  
Binding Studies ◽  
Specific Binding Sites ◽  
Kinin Receptors ◽  
Medullary Nuclei ◽  
Inferior Olivary

Kinins have been elected to the status of central neuromediators. Their effects are mediated through the activation of two G-protein-coupled receptors, denoted B1 and B2. Functional and binding studies suggested that B1 and B2 receptors are upregulated in the medulla and spinal cord of hypertensive and diabetic rats. The aim of this study was to localize and quantify kinin receptors in post-mortem human medulla obtained from normotensive, hypertensive, and diabetic subjects, using in vitro receptor autoradiography with the radioligands [125I]HPP-HOE140 (B2 receptor) and [125I]HPP[des-Arg10]-HOE140 (B1 receptor). Data showed specific binding sites for B2 receptor (0.4–1.5 fmol/mg tissue) in 11 medullary nuclei from 4 control specimens (paratrigeminal > ambiguus > cuneate, gelatinous layer of the caudal spinal trigeminal nucleus > caudal and interpolar spinal trigeminal, external cuneate, solitary tract > hypoglossal > gracile > inferior olivary nuclei). Increased density of B2 receptor binding sites was observed in seven medullary nuclei of four hypertensive specimens (paratrigeminal > external cuneate > interpolar and caudal spinal trigeminal, gracile, inferior olivary > hypoglossal nuclei). B2 receptor binding sites were seemingly increased in the same medullary nuclei of two diabetic specimens. Specific binding sites for B1 receptor (1.05 and 1.36 fmol/mg tissue) were seen only in the inferior olivary nucleus in two out of the ten studied specimens. The present results support a putative role for kinins in the regulation of autonomic, nociceptive, and motor functions at the level of the human medulla. Evidence is also provided that B2 receptors are upregulated in medullary cardiovascular centers of subjects afflicted of cardiovascular diseases.Key words: bradykinin, hypertension, diabetes, human brain.

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