Endogenous Blocker Research Articles

Decreased DANCR contributes to high glucose-induced extracellular matrix accumulation in human renal mesangial cell via regulating the TGF-β/Smad signaling.

Glomerulosclerosis is one of the major histopathologic changes in diabetic kidney diseases (DKD), which is characterized by excessive deposition of extracellular matrix (ECM) in the glomerulus mainly produced by mesangial cells in response to transforming growth factor-β (TGF-β) stimuli under diabetic conditions. Despite TGF-β has been implicated as a major pathogenic factor in the development of diabetic glomerulosclerosis, clinical trials of monoclonal antibodies against TGF-β failed to demonstrate therapeutic benefits. Thus, developing alternative therapeutic strategies to effectively block the TGF-β/Smad signaling could be of paramount importance for DKD treatment. Emerging evidence indicates that dysregulation of certain lncRNAs can lead to aberrant activation of TGF-β/Smad signaling. Herein, we identified a novel lncRNA, named DANCR, which could efficiently function as a negative regulator of TGF-β/Smad signaling in mesangial cells. Ectopic expression of DANCR could specifically block the activation of TGF-β/Smad signaling induced by high-glucose or TGF-β in human renal mesangial cells (HRMCs). Mechanistically, DANCR functions to stabilize nemo-like kinase (NLK) mRNA through interaction with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2), resulting in enhanced phosphorylating on the linker region of activated Smad2/3 in the nucleus. Taken together, our data have uncovered an lncRNA-based regulatory modality of the TGF-β/Smad signaling and identified DANCR as an endogenous blocker of TGF-β/Smad signaling in HRMCs, which may represent a potential therapeutic target against the diabetic glomerulosclerosis.

The deubiquitinating enzyme 13 retards non-alcoholic steatohepatitis via blocking inactive rhomboid protein 2-dependent pathway.

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway.

LEAP-2: An Emerging Endogenous Ghrelin Receptor Antagonist in the Pathophysiology of Obesity.

Liver-expressed antimicrobial peptide 2 (LEAP-2), originally described as an antimicrobial peptide, has recently been recognized as an endogenous blocker of growth hormone secretagogue receptor 1a (GHS-R1a). GHS-R1a, also known as ghrelin receptor, is a G protein-coupled receptor (GPCR) widely distributed on the hypothalamus and pituitary gland where it exerts its major functions of regulating appetite and growth hormone (GH) secretion. The activity of GHS-R1a is controlled by two counter-regulatory endogenous ligands: Ghrelin (activation) and LEAP-2 (inhibition). Ghrelin activates GHS-R1a on the neuropeptide Y/Agouti-related protein (NPY/AgRP) neurons at the arcuate nucleus (ARC) to promote appetite, and on the pituitary somatotrophs to stimulate GH release. On the flip side, LEAP-2, acts both as an endogenous competitive antagonist of ghrelin and an inverse agonist of constitutive GHS-R1a activity. Such a biological property of LEAP-2 vigorously blocks ghrelin’s effects on food intake and hormonal secretion. In circulation, LEAP-2 displays an inverse pattern as to ghrelin; it increases with food intake and obesity (positive energy balance), whereas decreases upon fasting and weight loss (negative energy balance). Thus, the LEAP-2/ghrelin molar ratio fluctuates in response to energy status and modulation of this ratio conversely influences energy intake. Inhibiting ghrelin’s activity has shown beneficial effects on obesity in preclinical experiments, which sheds light on LEAP-2’s anti-obesity potential. In this review, we will analyze LEAP-2’s effects from a metabolic point of view with a focus on metabolic hormones (e.g., ghrelin, GH, and insulin), and discuss LEAP-2’s potential as a promising therapeutic target for obesity.

Kir4.1/Kir5.1 channels possess strong intrinsic inward rectification determined by a voltage-dependent K+-flux gating mechanism.

Inwardly rectifying potassium (Kir) channels are broadly expressed in both excitable and nonexcitable tissues, where they contribute to a wide variety of cellular functions. Numerous studies have established that rectification of Kir channels is not an inherent property of the channel protein itself, but rather reflects strong voltage dependence of channel block by intracellular cations, such as polyamines and Mg2+. Here, we identify a previously unknown mechanism of inward rectification in Kir4.1/Kir5.1 channels in the absence of these endogenous blockers. This novel intrinsic rectification originates from the voltage-dependent behavior of Kir4.1/Kir5.1, which is generated by the flux of potassium ions through the channel pore; the inward K+-flux induces the opening of the gate, whereas the outward flux is unable to maintain the gate open. This gating mechanism powered by the K+-flux is convergent with the gating of PIP2 because, at a saturating concentration, PIP2 greatly reduces the inward rectification. Our findings provide evidence of the coexistence of two rectification mechanisms in Kir4.1/Kir5.1 channels: the classical inward rectification induced by blocking cations and an intrinsic voltage-dependent mechanism generated by the K+-flux gating.

CircNR3C1 Suppresses Bladder Cancer Progression through Acting as an Endogenous Blocker of BRD4/C-myc Complex

Bromodomain-containing protein 4 (BRD4), the core component of transcriptional regulatory elements, plays a significant role in tumorigenesis and aggressiveness. However, the mechanisms regulating the functions of BRD4 in bladder cancer (BC) still remain elusive. Herein, we identify one exonic circular RNA (circRNA) generated from NR3C1 gene (circNR3C1) as a regulator of BRD4/C-myc complex. Our previous study indicated that BRD4 and C-myc promoter region form a complex, allowing C-myc to function as a transcription factor for BC progression. In the present study, mechanism studies reveal that circNR3C1 could interact with BRD4 protein, dissociating the formation of BRD4/C-myc complex. In vivo, ectopic expression of C-myc partly reverses the tumorigenesis of xenografts circNR3C1-induced in nude mice. Conclusively, these results demonstrate that circNR3C1 inhibits BC progression through acting as endogenous blocker of BRD4/C-myc complex.

Differentiation of Murine C2C12 Myoblasts Strongly Reduces the Effects of Myostatin on Intracellular Signaling

Alongside in vivo models, a simpler and more mechanistic approach is required to study the effects of myostatin on skeletal muscle because myostatin is an important negative regulator of muscle size. In this study, myostatin was administered to murine (C2C12) and human (CHQ) myoblasts and myotubes. Canonical and noncanonical signaling downstream to myostatin, related ligands, and their receptor were analyzed. The effects of tumorkines were analyzed after coculture of C2C12 and colon cancer-C26 cells. The effects of myostatin on canonical and noncanonical signaling were strongly reduced in C2C12 cells after differentiation. This may be explained by increased follistatin, an endogenous blocker of myostatin and altered expression of activin receptor ligands. In contrast, CHQ cells were equally responsive to myostatin, and follistatin remained unaltered. Both myostatin administration and the coculture stimulated pathways associated with inflammation, especially in C2C12 cells. In conclusion, the effects of myostatin on intracellular signaling may be cell line- or organism-specific, and C2C12 myotubes seem to be a nonoptimal in vitro model for investigating the effects of myostatin on canonical and noncanonical signaling in skeletal muscle. This may be due to altered expression of activin receptor ligands and their regulators during muscle cell differentiation.

Efficacy of memantine in schizophrenic patients: A systematic review

IntroductionSeveral evidences support the hypothesis that glutamatergic dysfunction may be implicated in the pathogenesis of schizophrenia and in the last few year great interest has been focused on the role of the N-methyl-D-aspartate receptor (NMDAR). Memantine is a noncompetitive NMDARs antagonist, binds the same site of NMDARs of Mg2+, endogenous blocker of NMDARs, with moderate affinity, rapid unblocking kinetics and strong functional voltage-dependency. Memantine does not affect the physiological activation of NMDARs whereas it blocks the sustained activation under pathological conditions. Preclinical studies have demonstrated that memantine at high concentrations targets many receptors, including serotonin, nicotinic acetylcholine, sigma-1 and serotonin and dopamine receptors.ObjectivesIncreasing interest in memantine add-on therapy in schizophrenic patients with negative and cognitive symptoms may suggest that memantine could be a new promising treatment in schizophrenia.AimsThe aim of this update was to evaluate clinical data about the memantine effectiveness in schizophrenic patients.MethodsWe searched on PubMed to identify original studies about the use of memantine in treatment of schizophrenic patients. The search conducted on June 16th, 2016 yielded 135 records. Neuf papers met our inclusion criteria.ResultsNegative symptoms improved in the large majority of patients treated, however there is not a clear evidence on cognitive and positive symptoms (Table 1)ConclusionsMemantine therapy in schizophrenic patients has given unclear results. It seems that memantine improves mainly negative symptoms, while cognitive and positive symptoms did not improve significantly. Further trials with a more numerous sample are required obtain an objective result.Table 1Observation during Memantime administration.↓: reduction in severity of symptoms; -: no relevant modifications; +: onset of new symptomsDisclosure of interestThe authors have not supplied their declaration of competing interest.

MiR-130b, an onco-miRNA in bladder cancer, is directly regulated by NF-κB and sustains NF-κB activation by decreasing Cylindromatosis expression.

Persistent activation of NF-κB signaling is closely related to chronic inflammation and tumorigenesis. Commonly, NF-κB signaling is tightly controlled by multiple feedback loops and regulators, such as the deubiquitinases (DUBs). However, in cancer cells, NF-κB may override these feedbacks through special pathways and lead to the sustained activation. In the present study, we demonstrate that in transitional cell carcinoma (TCC) of bladder, miR-130b plays an oncogenesis role, it enhanced proliferation, invasion and migration of TCC cell, and was highly correlated with tumor progression. On the other hand, NF-κB directly regulated the transcription of miR-130b by binding with its promoter region. Importantly, we verify that, through deceasing the expression of Cylindromatosis (CYLD), a K63-specific DUB and endogenous blocker of NF-κB signaling, miR-130b can in return sustain the persistent activation of NF-κB, which may promote the malignant progression of TCC. Thus, the present study uncovers a potential signaling transduction in which NF-κB is continuously activated, and may provide a novel therapeutic approach for the clinical management of TCC.

Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

High-frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all isoforms in adult DRG, NaV1.6 is the main carrier of tetrodotoxin-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons, the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA-mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRG showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression, and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch-clamp recordings of tetrodotoxin-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current, effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6.

Механизмы положительной и отрицательной модуляции эффективности активации адренорецепторов и других рецепторов, ассоциированных с g-белком (Обзор литературы). Сообщение 3. Эндогенные блокаторы (ЭББАР, ЭБААР и ЭБМХР) как отрицательные модуляторы

Механизмы положительной и отрицательной модуляции эффективности активации адренорецепторов и других рецепторов, ассоциированных с g-белком (Обзор литературы). Сообщение 3. Эндогенные блокаторы (ЭББАР, ЭБААР и ЭБМХР) как отрицательные модуляторы

Effect of propranolol, histidine, and trimethylhydrazine propionate on the capacity of epinephrine to change the rate of erythrocyte agglutination.

We studied the effects of analogues of endogenous sensitizer of β-adrenergic receptors histidine (10(-4) g/ml) and mildronate (10(-5) g/ml) and endogenous β-adrenoreceptor blocker propranolol (10(-6) g/ml) on adrenoreactivity of erythrocytes in men assessed by changes in the rate of erythrocyte agglutination under the influence of epinephrine (10(-10)-10(-6) g/ml). Epinephrine increased the rate of agglutination, which attested to predominance of α1-adrenoceptors. Propranolol enhanced the effect of epinephrine, while histidine and mildronate reduced it. Hence, endogenous modulators of adrenoceptors can modify adrenoreactivity of erythrocytes and probably other cells, and erythrocytes can serve as indicator of instant adrenoreactivity of body cells.

An endogenous blocker of oxidized LDL

An endogenous blocker of oxidized LDL

Paradoxical Activation of an Inwardly Rectifying Potassium Channel Mutant by Spermine: "(B)locking" Open the Bundle Crossing Gate

Intracellular polyamines are endogenous blockers of inwardly rectifying potassium (Kir) channels and underlie steeply voltage-dependent rectification. Kir channels with strong polyamine sensitivity typically carry a negatively charged side chain at a conserved inner cavity position, although acidic residues at any pore-lining position in the inner cavity are sufficient to confer polyamine block. We have identified unique consequences of a glutamate substitution in the region of the helix bundle crossing of Kir6.2. Firstly, glutamate substitution at Kir6.2 residue F168 generates channels with intrinsic inward rectification that does not require blockade by intracellular polyamines or Mg(2+). In addition, these F168E channels exhibit a unique "spiked" tail phenotype, whereby large decaying inward tail currents are elicited upon spermine unbinding. This contrasts with the time-dependent recovery of current typically associated with blocker unbinding from ion channels. Interestingly, Kir6.2[F168E] channels exhibit a paradoxical biphasic conductance-voltage relationship in the presence of certain polyamines. This reflects channel blockade at positive voltages, channel stimulation at intermediate voltages, and exclusion of spermine from the pore at negative voltages. These features are recapitulated by a simple kinetic scheme in which weakly voltage-dependent spermine binding to a "shallow" site in the pore (presumably formed by the introduced glutamate at F168E) stabilizes opening of the bundle crossing gate. These findings illustrate the potential for dichotomous effects of a blocker in a long pore (with multiple binding sites), and offer a unique example of targeted modulation of the Kir channel gating apparatus.

Can We Identify Predictive Biomarkers for Antiangiogenic Therapy of Cancer Using Mathematical Modeling?

Can We Identify Predictive Biomarkers for Antiangiogenic Therapy of Cancer Using Mathematical Modeling?

Influence of the human blood serum on contractility and β-adrenoreactivity of the isolated human myocardium

On strips of the isolated myocardium of right hearts auriculum of the 43 patients with ischemic illness of heart and 9 patients with heart diseases of various ethyology at statement venous canule during aorto-coronary shunting, estimated influence of adrenaline (10(-9)-10(-4) g/ml) on amplitude caused by electrostimulus (1H, 5ms, 25-30 V) contractions, and also inotropic and adrenomodulation activity of serum blood (in dilution 1 : 10000, 1: 1000, 1 : 500, 1: 100, 1 : 50, 1: 10 and 1 : 5) nonpregnant women. Direct dependence of amplitude of contraction on size of fraction of of blood emission on Teyholts is revealed. It means, that strips of right auriculum myocardium reflect contractility of a left ventriculum myocardium. Adrenaline in concentration 10(-7)-10(-6) g/ml dependent of dose raised amplitude of the caused contraction not influencing it in concentration of 10(-9) and 10(-8) g/ml (the constant of dissotiation has 2 x 10(-7) g/ml), that as a whole, speaks about decrease in efficiency of activation beta-AP. Blood Serum in dissolutions 1 : 10000-1 : 50 did not influence on amplitude of contraction, and in dissolutions 1 : 10 and 1 : 5 strengthened it, that speaks presence in blood the endogenous activator of myocyte contractility (EAMC). Serum showed beta-adrenomodulation activity that speaks presence in it endogenous sensitizer of beta-adrenoreceptors (ESBAR) and endogenous blocker of beta-adrenoreceptors (EBBAR). In particular, in experiences with adrenaline in subthreshold concentration (10(-8) g/ml) serum showed ESBAR-activity (in dissolutions 1 : 1000, 1 : 500, 1 : 100 and 1 : 50), and in experiences with adrenaline in as much as possible effective concentration (10(-6) g/ml) serum showed ESBAR-activity (in dissolutions 1 : 50 and 1 : 10) and EBBAR-activity (in dissolutions 1:500) Hence, containing in blood serum endogenous modulators of beta-adrenoreactivity - ESBAR and EBBAR can modulate efficiency of beta-adrenoreceptors activation of human cardiomyocytes. It speaks about perspectivity of application of ES BAR analogues in cardiology.

Abstract LB-213: Plasma soluble VEGFR1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer

Abstract We explored plasma and urinary concentration of four members of the vascular endothelial growth factor (VEGF) family as potential response and toxicity biomarker of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The levels of VEGF, placental growth factor (PlGF) and soluble VEGF receptors 1 and −2 (sVEGFR1 and sVEGFR2) were measured by multiplex array in plasma and urine at baseline and during treatment. Pre-treatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment (evaluated histologically using ypT, Mandard and N scoring at surgery) as well as for all acute toxicities in patients with locally advanced rectal cancer treated prospectively from 2002 to 2008 with bevacizumab, 5-fluorouracil and radiation therapy prior to surgery in a phase I/II trial (N=32 patients). Of all biomarkers, the pretreatment plasma sVEGFR1 - an endogenous blocker of VEGF and a factor linked with “vascular normalization” - was strikingly associated with both tumor regression and with the number of adverse events after preoperative (neoadjuvant) bevacizumab and chemoradiation. Thus, plasma sVEGFR1 is a strong candidate as the first biomarker to stratify patients for bevacizumab therapy. Therefore, future studies of bevacizumab and/or cytotoxics should be further explore sVEGFR1 as biomarker in neoadjuvant setting as well as in metastatic disease. This study was partially supported by NIH grants R21-CA99237, P01-CA80124, R01-CA115767, R01-CA85140, R01-CA126642 and Federal Share/NCI Proton Beam Program Income grants, and by the National Foundation for Cancer Research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-213.

Voltage- and [ATP]-dependent Gating of the P2X2 ATP Receptor Channel

P2X receptors are ligand-gated cation channels activated by extracellular adenosine triphosphate (ATP). Nonetheless, P2X2 channel currents observed during the steady-state after ATP application are known to exhibit voltage dependence; there is a gradual increase in the inward current upon hyperpolarization. We used a Xenopus oocyte expression system and two-electrode voltage clamp to analyze this “activation” phase quantitatively. We characterized the conductance–voltage relationship in the presence of various [ATP], and observed that it shifted toward more depolarized potentials with increases in [ATP]. By analyzing the rate constants for the channel's transition between a closed and an open state, we showed that the gating of P2X2 is determined in a complex way that involves both membrane voltage and ATP binding. The activation phase was similarly recorded in HEK293 cells expressing P2X2 even by inside-out patch clamp after intensive perfusion, excluding a possibility that the gating is due to block/unblock by endogenous blocker(s) of oocytes. We investigated its structural basis by substituting a glycine residue (G344) in the second transmembrane (TM) helix, which may provide a kink that could mediate “gating.” We found that, instead of a gradual increase, the inward current through the G344A mutant increased instantaneously upon hyperpolarization, whereas a G344P mutant retained an activation phase that was slower than the wild type (WT). Using glycine-scanning mutagenesis in the background of G344A, we could recover the activation phase by introducing a glycine residue into the middle of second TM. These results demonstrate that the flexibility of G344 contributes to the voltage-dependent gating. Finally, we assumed a three-state model consisting of a fast ATP-binding step and a following gating step and estimated the rate constants for the latter in P2X2-WT. We then executed simulation analyses using the calculated rate constants and successfully reproduced the results observed experimentally, voltage-dependent activation that is accelerated by increases in [ATP].

Endogenous polyamines regulate cortical neuronal excitability by blocking voltage-gated Na+ channels.

Because the excitable properties of neurons in the neocortex depend on the characteristics of voltage-gated Na(+) channels, factors which regulate those characteristics can fundamentally modify the dynamics of cortical circuits. Here, we report on a novel neuromodulatory mechanism that links the availability of Na(+) channels to metabolism of polyamines (PAs) in the cerebral cortex. Using single channel and whole-cell recordings, we found that products of PA metabolism, the ubiquitous aliphatic polycations spermine and spermidine, are endogenous blockers of Na(+) channels in layer 5 pyramidal cells. Because the blockade is activity-dependent, it is particularly effective against Na(+) channels which fail to inactivate rapidly and thus underlie the persistent Na(+) current. At the level of the local cortical circuit, pharmacological depletion of PAs led to increased spontaneous spiking and periods of hypersynchronous discharge. Our data suggest that changes in PA levels, whether associated with normal brain states or pathological conditions, profoundly modify Na(+) channel availability and thereby shape the integrative behavior of single neurons and neocortical circuits.

Clozapine interacts with the glycine site of the NMDA receptor: Electrophysiological studies of dopamine neurons in the rat ventral tegmental area

Clozapine has a remarkable efficacy in treatment-resistant schizophrenia and is one of the most effective antipsychotic drugs used today. The clinical effects of clozapine are suggested to be related to a unique interaction with a variety of receptor systems, including the glutamatergic receptors. Kynurenic acid (KYNA) is an endogenous blocker of α7⁎ nicotinic receptors and a glutamate-receptor antagonist, preferentially blocking N-methyl- d-aspartate (NMDA) receptors. In the present in vivo electrophysiological study, changes in endogenous concentration of brain KYNA were utilized to analyze an interaction between clozapine and the glycine site of NMDA receptors. In control rats intravenously administered clozapine (0.078–10 mg/kg) increased the firing rate and the burst firing activity of dopamine (DA) neurons in the ventral tegmental area (VTA). Pretreatment with indomethacin (50 mg/kg, i.p., 1–3.5 h), a cyclooxygenase (COX)-inhibitor with a preferential selectivity for COX-1, which produced a significant elevation in brain KYNA levels, reversed the excitatory action of clozapine into an inhibitory response. In contrast, pretreatment with the COX-2 selective inhibitor parecoxib (25 mg/kg, i.v., 1–1.5 h) decreased brain KYNA formation and furthermore, clearly potentiated the excitatory effect of clozapine. Our results show that endogenous levels of brain KYNA are of importance for the response of clozapine on VTA DA neurons. On the basis of the present data we propose that clozapine is able to interact with glutamatergic mechanisms, via actions at the NMDA/glycine receptor.

Changes in the β-adrenergic and M-cholinergic modulating activities of the blood serum and urine in bronchial asthma

Biological tests showed that bronchial asthma is associated with decreased contents of the endogenous sensitizer of β-adrenoreceptors (ESBAR) and the endogenous blocker of M-cholinoreceptors (EBMCR) and an increased content of the endogenous blocker of β-adrenoreceptors (EBBAR) in the blood and urine of children and adults. These phenomena are considered to be causes of bronchial asthma.